A Phase III Double-blind, Randomised Study to Evaluate the Long-term Efficacy and Safety of Oxabact in Patients With Primary Hyperoxaluria
Phase: PHASE3
Conditions: Primary Hyperoxaluria
Sponsor: OxThera

Protocol OC5-DB-02 –Version 11 
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Clinical Study Protocol 
Oxalobacter formigenes (Oxabact) 
A Phase III Double-Blind, Randomized Study to Evaluate the Long-Term 
Efficacy and Safety of Oxabact in Patients with Primary Hyperoxaluria. 
Protocol Number 
Protocol Name  
EudraCT Number 
IND Number 
NCT Number
Sponsor: 
Sponsor signee: 
Protocol Date: 
Protocol Version: 
OC5-DB-02 
ePHex 
2017-000684-33 
15881 
NCT 03116685
OxThera Intellectual Property AB 
Regeringsgatan 111 
SE-111 39 Stockholm 
Sweden 
Bastian Dehmel, MD, Chief Medical Officer 
08 January 2021 
11 
- CONFIDENTIAL -
Information and data included in this study protocol contains trade secrets and privileged or confidential information 
which is the property of OxThera IP AB. No person is authorized to make it public without written permission of 
OxThera IP AB. These restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential.  This material may be disclosed to and used by your staff and associates as 
may be necessary to conduct the clinical study. 

Protocol OC5-DB-02 –Version 11 
 
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OxThera Intellectual Property AB 
IND 015881 
 
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Revision History 
Rev.: Version 
No. 
Description: 
Date: 
000 
1 
New document 
2016-04-13 
001 
2 
First draft revision in line with comments from EMA. 
2016-06-29 
002 
3 
Second draft revision 
2016-12-28 
003 
4 
Third draft revision  
2017-01-23 
004 
5 
Final protocol 
2017-02-10 
005 
6 
Amendment 1 – UK specific 
2017-06-27 
006 
7 
Amendment 2 
• Spain and Belgium added to list of participating 
countries. 
• Clarified that a separate Clinical Trial Application will 
be issued for the follow-up study. 
• Safety analyses will be done at a central lab instead of 
at the local lab.  
• Clarified process for patients with AKI during 
baseline.  
• Clarified that in the event there is a need to know the 
identity of the drug given to a patient, the decision to 
unblind the treatment resides solely with the 
investigator.  
• Minor corrections and clarifications.  
2017-09-21 
007 
8 
Amendment 3. 
• Reporting of Pregnancy during the study added to the 
Safety section. 
• Information added about the Data and Safety 
Monitoring Board. 
• Sample size section updated. 
• Schedule of assessments updated. 
2018-03-28 

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• The previous numbering of references (superscription 
format) have been replaced by Author name and year.  
• Reference list corrected and updated in alphabetical 
order. 
• Minor corrections and clarifications. 
008 
9 
Amendment 4 
• Secondary and exploratory endpoints have been 
reorganized. 
• Frequency of kidney stone events has been added 
under key secondary endpoints. 
• Information added that kidney stone events and related 
symptoms will be captured throughout the study. 
• Clarified that if an acute kidney injury/stone event  
occurred close to a scheduled visit, the visit would be 
rescheduled once the AKI/stone event was resolved. 
• Tunisia added to list of participating countries. 
• Statistical sections updated in line with revised 
endpoints. 
• Minor corrections and clarifications. 
 
15 October 
2018 
009 
9.1 
Amendment 5  
• Clarification that for determination of eligibility, 
estimated Glomerular Filtration Rate (eGFR) can be 
calculated using Schwartz or CKD-EPI equations that 
include serum creatinine and/or cystatin C. 
Please note, that Amendment 5 was a country-specific 
Amendment for Spain and the US. 
06 Sept 
2019 
010 
10 
Amendment 6 
• Includes revisions made in Amendment 5. 
• Implementation of post-treatment safety follow-up 
(mainly addressed in sections 6.2 and 6.3). 
Consequently, the definition of “End-of-Study” was 
updated and “End-of-Treatment” was defined.  
• Updated section 7.4. Withdrawal criteria to include 
“The subject requires dialysis”  
19 Dec 
2019 

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• Updated list of blind data and added clarifications in 
section 8.4. 
• Updated section 11.4 Reporting of Adverse Events to 
harmonise with the Safety Management plan for this 
study (Vs 4.0 dated 24 Jun 2019). 
• Updated section 11.5.3 to refer to Investigator 
Brochure; this was to harmonise with the protocol of 
the OC5-OL-01 and OC5-OL-02 studies. 
• Added updates and clarifications in section 12 
Statistical Methods including tests of hypotheses and 
significance levels, information on methods used to 
analyse endpoints and definition of treatment-
emergent AEs. Added additional subgroups. 
• Minor updates, corrections and clarifications 
throughout the protocol. 
011 
11 
Amendment 7 
• Added clinical success criteria in section 5.3 
• Updated section 7.4. Withdrawal criteria to clarify 
which assessments should be done for early 
withdrawal. 
•  Added 2 new other endpoints (Percent change from 
baseline in total plasma oxalate concentration and 
Subjects achieving ‘near-normalization’ in total 
plasma oxalate concentration) in section 10. 
• Added updates and clarifications in section 12 relating 
to hierarchial testing. 
• Updated OC5-OL-01 study information throughout the 
protocol. 
• Minor updates, corrections and clarifications 
throughout the protocol. (N.B. “Patient” has been 
replaced with “subject” throughout the protocol as 
appropriate).   
 
08 Jan 2021 
 
 
 

Protocol OCS-DB-02, Confidential 
Study protocol approval 
Protocol number: 
OCS-DB-02 
Protocol Date: 
08 January 202 1 
Protocol Version: 
11 
Study title: 
A phase III double-blind, randomized study to evaluate the long-term efficacy 
and safety of Oxabact in patients with primary hyperoxaluria. 
Sponsor: 
OxThera Intellectual Property AB 
Regeringsgatan 111 
SE-111 39 Stockholm 
Sweden 
This protocol bas been approved by: 
Bastian Dehmel, MD 
Chief Medical Officer 
OxThera AB, Stockholm, Sweden 
Sponsor's representative 
Signatm·e: 
Date: 
(DD - MMM - YYYY) 
Dr Gesa Schalk 
Coordinating Investigator 
Kindernierenzentrum Bonn, 1,tnnany /41 
Signature: 
U 
--v---~-----------
oate: 
/( 2 --
'1 AN 
Z-0 2-d 
(DD -MMM - YYYY{J 
Protocol rev 0 11 
08 Januaiy 2021 
Page 5 of 92 

Protocol OC5-DB-02 –Version 11 
 
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Procedures in Case of Emergency 
 
 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Telephone number 
Fax number 
Drug Safety / Medical 
Monitor 
 Yves Miclo 
+44 1223 402660 
+44 1223 413689 
Clinical Study Leader at 
sponsor 
Maria Norling 
+46 73 987 00 78 
 
 
 
 
 

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1 SYNOPSIS 
 
Name of Sponsor/Company: 
OxThera IP AB 
Name of Investigational Product: 
Oxabact (OC5) 
Name of Active Ingredient: 
Oxalobacter formigenes, strain HC-1 
Title of Study:  
A phase III double-blind, randomized study to evaluate the long-term efficacy and safety of 
Oxabact in patients with primary hyperoxaluria.  
Planned Number of Sites/Countries  
The study is planned to be conducted in the following countries: 
Germany, USA, France, UK, the Netherlands, Spain, Belgium, Tunisia. 
9-11 sites will be participating.  
Phase of Development:  
III 
Objectives:  
Primary: 
o To evaluate the efficacy of Oxabact following 52 weeks treatment in patients with 
maintained kidney function but below the lower limit of the normal range (eGFR 
< 90 ml/min/1.73 m2) and a total plasma oxalate concentration ≥ 10 μmol/L. 
Secondary: 
o To obtain additional safety data from 52 weeks continuous treatment with Oxabact. 
Clinical Success Criteria for total plasma oxalate 
Oxabact will be considered associated with a clinically meaningful treatment effect on total 
plasma oxalate, if the results meet the following criteria:  
 
1. Statistically significant difference in change from baseline for total plasma oxalate 
concentration between Oxabact and placebo in favor of Oxabact after 52 weeks of 
treatment.  
AND 
2. Estimated difference in absolute change from baseline for total plasma oxalate 
concentration between Oxabact and placebo of ≥5 μmol/L after 52 weeks of treatment.  
OR  

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Estimated difference in percent change from baseline for total plasma oxalate 
concentration between Oxabact and placebo of ≥30% after 52 weeks of treatment.   
AND 
3. Greater percentage of subjects in the Oxabact arm than in the placebo arm achieving 
near-normalization of total plasma oxalate concentration (< 10 μmol/L) at least twice 
during weeks 24 to 52 of treatment.  
 
 
Methodology:  
This double-blind, randomized international multi-center study will evaluate the efficacy and 
safety of OC5 in patients with PH. The study will enrol subjects with maintained renal function 
but with an eGFR below the lower limit of the normal ranges (<90 ml/min/1.73 m2) and a total 
plasma oxalate concentration ≥ 10 μmol/L.  
During the screening/baseline period of up to 8 weeks, in total 3 visits will be made. Visit 1 will 
be the screening visit. Information on historical renal function (including eGFR, serum 
creatinine and equation used to calculate historic eGFR) and kidney stone events (prior to 
informed consent) will be collected at the screening visit. For subjects under 18 years of age and 
subjects that were <18 years up to 3 years prior to screening (i.e. for all subjects under 21 years 
at screening), height used to calculate historic eGFR will also be collected. During the baseline 
period, samples will be taken for analysis of plasma oxalate, serum creatinine and serum 
cystatine C. Serum will also be analysed for magnesium, phosphorus, citrate, calcium, 
glycolate, ALP, bicarbonate, CRP, WBC and blood urea nitrogen (BUN).  
During the baseline period, two echocardiography (Speckle Tracking and traditional) 
examinations will be done as well as one ultrasound of the kidney. Patient Quality of Life will 
be evaluated using a questionnaire. Two 24-hour urine samples will be taken for determination 
of magnesium, phosphorus, citrate, calcium, glycolate, urea, creatinine, calcium oxalate 
crystals, pH, osmolality, urinary volume and oxalate excretion and one stool sample will be 
analysed for number of O. formigenes. The urine and stool samples will be taken at the 
subjects´s home during the baseline period. Information on stone events and related symptoms 
will be collected during visits 2 and 3 of the baseline period. 
After the baseline period (at visit 3), eligible subjects will be randomized to start on twice daily 
dosing of Oxabact or placebo in a 1:1 ratio. Subjects will be stratified in a first step in an attempt 
to evenly distribute PH type 2/type 3 patients, if the subject is not PH type 2 or PH type 3, the 
subject will be stratified for baseline urinary oxalate excretion above or below or equal to 
1.87 mmol/24h/1.73 m2 (based on the mean of the two values from screening/baseline).  
Randomized subjects will have visits to the clinic at week 8, 16, 24, 32, 40, 48 and 52. Plasma 
sample will be collected at week 8, 16, 24, 32, 40, 48 and 52. Subjects will be asked to provide 
24-hour urine collections at week 8, 24, 40 and 52 and faecal samples at weeks 24, 40 and 52. 
Echocardiography will be performed at week 24 and 48 and ultrasound of the kidney at week 
48. Safety evaluation will include physical examination and safety labs at week 8, 16, 24, 32, 
40, 48 and 52. Patient Quality of Life will be evaluated using a questionnaire at week 8, 24, 
40 and 52. After the treatment phase, subjects will be followed for safety for 2 weeks or until 
the day before first dose date in the follow-up study OC5-OL-02, whichever occurs first.  

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Adverse events and concomitant medication will be monitored throughout the study. 
Information on kidney stone events and related symptoms occurring between signature of the 
informed consent form and the end of study will be captured. 
In the case of an acute kidney injury (AKI) /kidney stone event occurring close to a scheduled 
visit, the visit will be rescheduled after resolution of the AKI/stone event.  
 
 
Illustration of the Study Design: 
 
 
 
 
Screening/ Baseline 
(up to 8 weeks) 
Treatment  
(52 weeks) 
Post-
treatment  
safety 
follow-up 
(up to 2 
weeks) 
Week 
-8-01 
0 
8 
16 
24 
32 
40 
48 
52 
 
Visit 
number 
1 
2 
3 
TS2 
4 
5 
6 
7 
8 
9 
10 
NA 
Plasma 
oxalate 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
eGFR3 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Stone 
events4,5 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocard.6 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
Safety labs7 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Stool 
X8 
 
 
 
X 
 
X 
 
X 
 
24h urine 
collection 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Ultrasound  
 
 
X 
 
 
 
 
 
 
X 
 
 
Quality of 
Life 
X8 
 
X 
 
X 
 
X 
 
X 
 
Adverse 
Events5 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
1All relevant assessments during screening/baseline will be completed during week -8 - 0, in total 2 visits will be  
done before baseline visit 3. The visits should be scheduled at least two weeks apart during the baseline period (visit 
1, 2 and 3). After randomization of the subject, study drug will be ordered and shipped to the subject for start of 
treatment.  
2Treatment Start (TS) - visit weeks in the Treatment period will be calculated starting from treatment day one. 
3As determined by the Schwartz equation eGFR for children (age below 18), and CKD-EPI equation for adults (age 
18 or above) based on serum creatinine. For determination of eligibility, eGFR can be calculated using Schwartz or 

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CKD-EPI equations that include serum creatinine and/or cystatin C. 
4Kidney stone events and related symptoms will be captured at every visit, including occurrences in between visits. 
5A post-treatment safety follow-up will be performed as a telephone call (see Section 6.3.4 for details). 
6Two echocardiography examinations at least three weeks apart should be performed during the baseline period 
(week -8 – 0). The week 24 and 48 examination should be done within +/- 2 weeks of the clinic visit. If the images 
at week 24 and/or 48 do not meet quality criteria, the examination will be repeated within 4 weeks.  
7Safety labs will include blood and urine sampling. 
8Can be done anytime during screening/baseline, i.e. week -8 – 0. 

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Number of Subjects (planned):  
Approximately 22 subjects will be randomized in the study to Oxabact or placebo in a 1:1 ratio; 
approximately 11 subjects will be treated with Oxabact and 11 subjects with placebo. This is to 
ensure that 18 subjects complete the 52-week treatment period. Screen failures may be 
rescreened at the discretion of the investigator. 
 
Inclusion Criteria: 
1. Signed informed consent (as applicable for the age of the subject) 
2. A diagnosis of PH (as determined by standard diagnostic methods).  
3. eGFR < 90 ml/min/1.73 m2. The Schwartz equation will be used to estimate GFR for 
children (age below 18), and CKD-EPI equation will be used for adults (age 18 or 
above). 
4. Plasma oxalate concentration ≥10 μmol/L in total plasma oxalate. 
5. Male or female subjects ≥ 2 years of age. 
6. Subjects receiving vitamin B6 must be receiving a stable dose for at least 3 months prior 
to screening and must not change the dose during the study. Subjects not receiving 
vitamin B6 at study entry must be willing to refrain from initiating pyridoxine during 
study participation.  
 
Exclusion Criteria: 
7. Inability to swallow size 4 capsules. 
8. Subjects that have undergone transplantation (solid organ or bone marrow). 
9. Subjects requiring dialysis or at immediate risk for kidney failure or expected to be in 
need of dialysis during the study period.  
10. The existence of secondary hyperoxaluria, e.g. hyperoxaluria due to bariatric surgery or 
chronic gastrointestinal diseases such as cystic fibrosis, chronic inflammatory bowel 
disease and short-bowel syndrome. 
11. Use of antibiotics to which O. formigenes is sensitive. (This includes current antibiotic 
use, or antibiotics use within 14 days of initiating study medication.) 
12. Current treatment with a separate ascorbic acid preparation. 
13. Pregnant women (or women who are planning to become pregnant) or lactating women. 
14. Women of childbearing potential who are not using adequate contraceptive precautions.  
15. Presence of a medical condition that the Investigator considers likely to make the subject 
susceptible to adverse effect of study treatment or unable to follow study procedures or 
any condition that is likely to interfere with the study drug mechanism of action (such as 
abnormal GI function).  
16. Participation in any interventional study of another investigational product, biologic, 
device, or other agent within 60 days prior to the first dose of OC5 or not willing to 
forego other forms of investigational treatment during this study. 
 

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Investigational Product, Dosage and Mode of Administration:  
The study drug consists of Oxabact. The dose will be administered orally as one enteric-
coated size-4 capsule with breakfast and dinner twice daily. The dose will be NLT 1E+09 
colony forming units (CFU) per capsule. Placebo capsules of same size and with the same 
bulking agent will be used in the study.  
 
Duration of Treatment:  
Subjects will be treated for 52 weeks with Oxabact or placebo.  
The subjects will be offered to continue in an open-label follow-up protocol with Oxabact 
treatment directly after the 52 weeks treatment period. 
 
 
Criteria for Evaluation: 
Efficacy evaluation will be based on the following parameters: 
 
 
Primary Endpoint 
 Change from baseline in total plasma oxalate concentration after 52 weeks of 
treatment.  
Key Secondary Endpoints 
 Change from baseline in kidney function (eGFR) after 52 weeks of treatment.  
 Frequency of kidney stones events after 52 weeks of treatment. Stone events are 
defined as:  
o Subject- or investigator reported symptoms, or  
o Stone passages or removals, or 
o Increase in number of stones assessed by ultrasound 
Other Endpoints 
 Percent change from baseline in total plasma oxalate concentration after 52 weeks of 
treatment. 
 Subjects achieving ‘near-normalization’ of total plasma oxalate concentration (<10 
µmol/L) at least twice during weeks 24 to 52 of treatment.  
 Change from baseline in myocardial function as measured by Speckle Tracking and 
traditional echocardiography. 
 Change from baseline in free plasma oxalate concentration after 52 weeks of 
treatment. 

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 Change from baseline in urinary oxalate excretion after 52 weeks of treatment.  
 Change from baseline in grade of nephrocalcinosis as assessed by Ultrasound. 
 Change in number of O. formigenes in stool. 
 Association between change in number of O. formigenes in stool and change in total 
plasma oxalate concentration.  
 Change from baseline in score of Quality of Life questionnaire.  
 Change from baseline in markers for renal function, renal tubular capacity and 
inflammation:  
Urine: magnesium, phosphorus, citrate, calcium, glycolate, creatinine, urea, calcium 
oxalate crystals, pH, osmolality and urinary volume.  
Blood: magnesium, phosphorus, citrate, calcium, glycolate, BUN, ALP, bicarbonate, 
CRP, WBC, creatinine and cystatine C. 
Safety: 
Adverse events (AEs), vital signs, physical examination, hematology, clinical chemistry, 
urinalysis. 
 
Statistical Methods: 
 
Sample Size Calculation 
In a previous OxThera study OC3-DB-02, with a total of 11 subjects (7 on active treatment, 4 
on placebo) having a baseline eGFR <90 ml/min/1.73 m2, a mean difference from baseline 
(screening) in total plasma oxalate concentration of - 4.964 (SD=5.219) μmol/L between 
active treatment versus placebo was observed after 24 weeks of treatment. Furthermore, 
OxThera study OC5-DB-01 showed a mean difference in total plasma oxalate of -5.299 
(SD=3.235) after 8 weeks of treatment in a total of 9 subjects (7 active, 2 placebo) in subjects 
with baseline eGFR <90 ml/min/1.73 m2. 
 
Since for study OC5-DB-02 multiple plasma oxalate measurements will be taken at visits 1, 
2, 3, 4, 5, 6, 7, 8, 9 and 10, the most appropriate statistical model for the primary endpoint is a 
mixed effect repeated measures model (MRMM). It is expected that at week 52 the difference 
may be larger than what has been observed in the previous study OC5-DB-01 at 8 weeks. 
Therefore, for the calculation a conservative mean difference of -5.50 with SD of 4.00 is 
assumed. Using the MRMM model in a two-sided approach with α=5%, β=10% (and thus 
power=90%), a 1:1 allocation ratio and assuming a within subject correlation of 0.70, the 
sample size is assessed at 9 subjects for each group. With this sample size, a difference of -
6.00 with an SD of 4.50 may be considered to be statistically significant (Oxabact vs. 
Placebo). Considering 18 completers are needed based on this calculation, an estimate of 22 
subjects will be randomized to account for possible drop-outs. 
 
 
 

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To account for the possiblity of higher than observed variability, please find below sample size 
estimates for various configurations. 
 
Sample Size Calculation 
Primary endpoint plasma oxalate 
  
                Difference in plasma oxalate between Oxabact and Placebo 
SD 
-4.50 
-5.00 
-5.50 
-6.00 
-6.50 
-7.00 
3.00 
7:7 
6:6 
5:5 
4:4 
4:4 
3:3 
3.50 
10:10 
8:8 
7:7 
6:6 
5:5 
4:4 
4.00 
13:13 
10:10 
9:9 
7:7 
6:6 
6:6 
4.50 
16:16 
13:13 
11:11 
9:9 
8:8 
7:7 
5.00 
20:20 
16:16 
13:13 
11:11 
10:10 
8:8 
5.50 
24:24 
19:19 
16:16 
14:14 
12:12 
10:10 
  
Key secondary endpoint eGFR 
Using a MRMM model in a two-sided approach with α=5%, and a within subject correlation 
of 0.70, the sample size evaluated at 9 subjects for each group yields approximately 90% 
power to identify a difference (SD) of 4 (3) ml/min/1.73m2 in eGFR change from baseline at 
week 52 between the treatment arms. 
 
Primary Endpoint 
Change from baseline in total plasma oxalate concentration will be calculated at each visit as 
the visit value minus the mean of the three measurements during baseline. Analysis of total 
plasma oxalate will be considered as the primary analysis. The primary statistical analysis 
will be performed using a mixed-effect repeated-measures model analysis based on the full 
analysis set (FAS) with a model that includes the following fixed effects: treatment group, 
baseline total plasma oxalate value, baseline stratum (PH type 2, PH type 3, not PH type 2 or 
3 and baseline urinary oxalate excretion ≤ 1.87 mmol/24h/1.73 m2, not PH type 2 or 3 and 
baseline urinary oxalate excretion > 1.87 mmol/24h/1.73 m2), week, and week-by-treatment 
interaction. The primary comparison will be between the Week 52 changes from baseline in 
OC5 and placebo. Unstructured covariance matrix will be used in the model. An 
autoregressive of order 1 (AR (1)) variance covariance matrix will be used for the within 
subject variation in the MRMM. In case there is a convergence problem, alternative variance 
covariance matrix structures will be used. 
 
Mean total plasma values over time for both treatment groups will be plotted in addition to a 
plot with the data over time presenting one line for each subject. Additionally, and for each 
subject a plot presenting both total plasma oxalate and eGFR over time will be produced to 
illustrate how total plasma oxalate and eGFR change together.  

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A sensitivity analysis will also be performed using multiple imputations (MI) prior to 
applying the MRMM. 
An additional sensitivity analyses to assess the robustness of the primary analysis to possible 
deviations from the missing at random (MAR) assumption will be performed. A pattern-
mixture model (PMM) will be used to evaluate the possibility of the missing pattern being 
missing not at random (MNAR).  
Additionally, a second analytical method approach will be provided as supportive analyses 
(i.e. ANCOVA and/or AUC) and will be further defined in the SAP. 
Secondarily the same analysis will be produced based on the per protocol analysis (PP) set. 
Key Secondary Endpoints 
Change from baseline in kidney function (i.e. eGFR slope) after 52 weeks of treatment will be 
analysed in the same way as the primary endpoint. Estimated GFR will be calculated for the 
primary analysis based on the 2009 creatinine-based “Schwartz bedside” equation (for 
children below 18 years of age) and 2009 creatinine-based CKD-EPI equation for adults. 
Historical renal function will be assessed in the context of on-study renal function to 
determine the degree of progression of renal function decline (i.e. the slope) before and 
during the study.   
Kidney stone events after 52 weeks of treatment will be summarized using descriptive 
statistics. Incidence rates and 95% CIs of kidney stone events (defined as the number of 
events divided by the total person-years) will be calculated along with the number of stone 
events and the number of subjects with a stone event. Treatment groups will be compared. 
Other Endpoints 
• Percent change from baseline in total plasma oxalate concentration after 52 weeks 
of treatment will be analyzed in the same way as the primary endpoint. 
• Subjects achieving ‘near-normalization’ of total plasma oxalate concentration (<10 
µmol/L) at least twice during weeks 24 to 52 of treatment will be summarized. The 
treatment arms will be compared using the stratified generalized Cochran-Mantel-
Haenszel test of general association including the appropriate stratification factors. 
Exact 95% CIs will be calculated for each treatment arm, and the common odds 
ratio across strata for the treatment arms. Wilson’s score method with continuity 
correction will be used to calculate a 95% CI for the difference in rates. 
• Change from baseline in myocardial function as measured by Speckle Tracking and 
traditional echocardiography will be summarized descriptively over time. 
• Change from baseline in free plasma oxalate after 52 weeks of treatment will be 
analysed in the same way as the primary endpoint.  
• Change from baseline in urinary oxalate excretion after 52 weeks of treatment will 
be analysed in the same way as the primary endpoint. 
• Change from baseline in grade of nephrocalcinosis as assessed by ultrasound will 
be summarized. 

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• 
Change in number of O. formigenes in stool will be based on number of O. 
formigenes at week 52 compared to baseline in the active group versus placebo. 
• 
Association between change in number of O. formigenes in stool and change in 
total plasma oxalate concentration will be evaluated.  
• 
Change from baseline in score of Quality of Life scores as measured by SF36V2 
or CHQ/PF50 questionnaires, depending on age, will be summarized over time 
and compared descriptively between the two treatment groups 
• Change from baseline in markers for renal function, renal tubular capacity and 
inflammation:  
Urine: magnesium, phosphorus, citrate, calcium, glycolate, creatinine, urea, 
calcium oxalate crystals, pH, osmolality and urinary volume.  
Blood: magnesium, phosphorus, citrate, calcium, glycolate, BUN, ALP, 
bicarbonate, CRP, WBC, creatinine and cystatine C. 
 
Subgroup Analyses 
Subgroup analyses for total and free oxalate concentration, eGFR, urine oxalate, stone events, 
O. formigenes in stool, Speckle Tracking and traditional echocardiography) will be performed 
in the following subgroups of subjects, provided there is sufficient sample size: 
o Subjects with a baseline urinary oxalate excretion above and equal to or 
below 1.87 mmol/L/24h/1.73 m2 respectively (mean of the two values 
during screening/baseline). 
o Subjects above or equal to and below 18 years of age at baseline.       
o Subjects with a baseline eGFR above or equal to and below 60 
ml/min/1.73m2 respectively (mean of the obtained values during 
screening/baseline calculated by the 2009 creatinine-based “Schwartz 
bedside” equation for children (below 18 years of age) and the 2009 
creatinine-based CKD-EPI equation for adults). 
o Race.     
o Gender.  
o Progressors and non-progressors based on historic eGFR (i.e. eGFR prior 
to treatment start)  
o Use of vitamin B6 at baseline 
 
Statistical Method Safety:  
The safety will be summarized using descriptive statistics based on frequency, seriousness, 
relationship and severity of treatment-emergent AEs. Clinically relevant changes in safety 
laboratory parameters, vital signs, and physical examinations will also be summarized. 
 

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2 TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
1 
SYNOPSIS........................................................................................................................................................ 7 
2 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................................... 17 
2.1 
List of Tables ................................................................................................................................................................ 20 
2.2 
List of Figures ............................................................................................................................................................. 20 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................... 21 
4 
INTRODUCTION ........................................................................................................................................ 23 
4.1 
Primary Hyperoxaluria ............................................................................................................................................ 23 
4.1.1 
Aetiology, Clinical Features and Epidemiology .................................................................................. 23 
4.1.2 
Unmet Medical Need .................................................................................................................................... 24 
4.2 
Oxabact ........................................................................................................................................................................... 24 
4.3 
Oxabact Treatment for PH Patients .................................................................................................................... 24 
4.4 
Clinical Experience with Oxabact ....................................................................................................................... 25 
4.4.1 
Clinical Experience in PH Patients .......................................................................................................... 28 
4.5 
Rationale for Current Phase III Study ............................................................................................................... 35 
4.5.1 
Overall Objective ........................................................................................................................................... 35 
4.5.2 
OC5 Development ......................................................................................................................................... 36 
4.5.3 
Dose Justification .......................................................................................................................................... 37 
4.6 
Overall Risk and Benefit Assessment .................................................................................................................. 38 
4.6.1 
Burden ............................................................................................................................................................... 38 
4.6.2 
Risk Threshold ............................................................................................................................................... 38 
4.6.3 
Benefits ............................................................................................................................................................. 39 
4.6.4 
Benefit: Risk Assessment............................................................................................................................ 39 
5 
TRIAL OBJECTIVES AND PURPOSE ................................................................................................ 41 
5.1 
Primary Objective ....................................................................................................................................................... 41 
5.2 
Secondary Objectives ................................................................................................................................................ 41 
5.3 
Clinical Success Criteria for total plasma oxalate ....................................................................................... 41 
6 
INVESTIGATIONAL PLAN .................................................................................................................... 42 
6.1 
Background and Rationale. ..................................................................................................................................... 42 
6.2 
Overall Study Design and Plan ............................................................................................................................. 43 
6.3 
Schedule of Assessments .......................................................................................................................................... 46 
6.3.1 
Screening .......................................................................................................................................................... 48 
6.3.2 
Baseline ............................................................................................................................................................ 49 
6.3.3 
Treatment Period ........................................................................................................................................... 50 
6.3.4 
Follow Up ........................................................................................................................................................ 51 
6.3.5 
Electronic Patient Reported Outcome ..................................................................................................... 51 
6.4 
Specimen Collection at Subjects’ Homes .......................................................................................................... 51 
6.5 
Diet .................................................................................................................................................................................... 51 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................................................... 53 
7.1 
Subject Inclusion Criteria. ....................................................................................................................................... 53 
7.2 
Subject Exclusion Criteria ...................................................................................................................................... 53 
7.3 
Contraceptive Precautions ...................................................................................................................................... 53 

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7.4 
Subject Withdrawal Criteria .................................................................................................................................. 54 
8 
TREATMENT OF SUBJECTS ................................................................................................................ 56 
8.1 
Description of Study Treatment ............................................................................................................................ 56 
8.2 
Concomitant Medications ........................................................................................................................................ 56 
8.2.1 
Concomitant Treatment with Vitamin B6.............................................................................................. 56 
8.2.2 
Prohibited Medications ................................................................................................................................ 56 
8.3 
Treatment Compliance .............................................................................................................................................. 57 
8.4 
Randomization and Blinding .................................................................................................................................. 57 
9 
STUDY DRUG MATERIALS AND MANAGEMENT ...................................................................... 58 
9.1 
Study Drug ..................................................................................................................................................................... 58 
9.2 
Study Drug Packaging and Labelling ................................................................................................................ 58 
9.3 
Study Drug Storage .................................................................................................................................................... 58 
9.4 
Study Drug Accountability, Handling and Disposal .................................................................................... 58 
10 
ASSESSMENT OF EFFICACY ............................................................................................................... 60 
10.1 
Plasma Oxalate ............................................................................................................................................................ 60 
10.2 
Kidney Function Parameters ................................................................................................................................. 61 
10.3 
Kidney Stone Events. .................................................................................................................................................. 62 
10.4 
Speckle Tracking and Traditional Echocardiography ................................................................................ 62 
10.5 
Quality of Life Questionnaire ................................................................................................................................ 63 
10.6 
Other Parameters for Evaluation of Treatment Effect ................................................................................ 63 
10.6.1 
Quantification of O. formigenes .......................................................................................................... 63 
10.6.2 
Ultrasound .................................................................................................................................................. 64 
10.6.3 
Twenty-Four-Hour Urine Samples ..................................................................................................... 64 
10.6.4 
Plasma Sample – Other Endpoints ...................................................................................................... 64 
11 
ASSESSMENT OF SAFETY..................................................................................................................... 65 
11.1 
Definition of Adverse Events .................................................................................................................................. 65 
11.2 
Relationship to Study Drug ..................................................................................................................................... 66 
11.3 
Recording Adverse Events ....................................................................................................................................... 67 
11.4 
Reporting Adverse Events. ....................................................................................................................................... 68 
11.4.1 
Emergency Unblinding ........................................................................................................................... 69 
11.5 
Anticipated Adverse Events .................................................................................................................................... 69 
11.5.1 
Review of Available Data ...................................................................................................................... 69 
11.5.2 
Safety Data for OC5-DB-01 Study ..................................................................................................... 70 
11.5.3 
Safety Data for the OC5-OL-01 Study .............................................................................................. 72 
11.5.4 
Systemic Infections due to O. formigenes ........................................................................................ 72 
11.5.5 
Elevated Levels of Plasma Formate ................................................................................................... 72 
11.6 
Laboratory Safety Measurements. ........................................................................................................................ 73 
11.7 
Vital Sign Measurements ......................................................................................................................................... 73 
11.8 
Physical Examinations .............................................................................................................................................. 73 
11.9 
Pregnancy ...................................................................................................................................................................... 74 
11.10 
Data and Safety Monitoring Board ................................................................................................................ 74 
12 
STATISTICAL METHODS ...................................................................................................................... 75 
12.1 
Study Populations ....................................................................................................................................................... 75 
12.2 
Tests of Hypotheses and Significance Levels .................................................................................................. 75 
12.3 
Sample Size Calculation ........................................................................................................................................... 75 
12.4 
Primary Endpoint........................................................................................................................................................ 77 
12.5 
Key Secondary Endpoints ........................................................................................................................................ 77 

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12.6 
Other Endpoints ........................................................................................................................................................... 78 
12.7 
Subgroup Analysis ...................................................................................................................................................... 79 
12.8 
Safety ................................................................................................................................................................................ 80 
12.9 
Randomization .............................................................................................................................................................. 80 
12.10 
Demographics and Baseline Characteristics............................................................................................. 80 
12.11 
Statistical Analysis ................................................................................................................................................ 80 
12.11.1 
Data Imputation ........................................................................................................................................ 80 
13 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................. 81 
14 
QUALITY CONTROL AND QUALITY ASSURANCE.................................................................... 82 
14.1 
Monitoring and Audits .............................................................................................................................................. 82 
14.2 
Site Personnel ............................................................................................................................................................... 82 
15 
ETHICS AND REGULATORY REQUIREMENTS .......................................................................... 83 
15.1 
Ethics Review ................................................................................................................................................................ 83 
15.2 
Ethical Conduct of the Study .................................................................................................................................. 83 
15.3 
Written Informed Consent ....................................................................................................................................... 83 
15.4 
Regulatory Requirements. ........................................................................................................................................ 83 
16 
DATA HANDLING AND RECORDKEEPING ................................................................................... 85 
16.1 
Case Report Forms. .................................................................................................................................................... 85 
16.2 
Retention of Records .................................................................................................................................................. 85 
16.3 
Protection of Personal Data. .................................................................................................................................. 85 
17 
FINANCING, INDEMNIFICATION AND INSURANCE ................................................................ 86 
18 
CONFIDENTIALITY, INTELLECTUAL PROPERTY AND PUBLICATION POLICY ....... 87 
19 
CHANGES TO THE STUDY PROTOCOL .......................................................................................... 88 
20 
REFERENCES.............................................................................................................................................. 89 
21 
APPENDICES ............................................................................................................................................... 91 

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2.1 List of Tables 
Table 1: Emergency Contact Information ....................................................................................... 6 
Table 2: Abbreviations and Specialist Terms ............................................................................... 21 
Table 3: Summary of Clinical Studies .......................................................................................... 26 
Table 4: Factors Univariately Associated with Incident ESRD among PH Patients 
without ESRD at Diagnosis ....................................................................................... 42 
Table 5: Schedule of Assessments ................................................................................................ 46 
Table 6: Details of the Study Drug in the OC5-DB-02 Study ...................................................... 58 
Table 7: WHO-UMC Causality Categories .................................................................................. 66 
Table 8: Overview of Adverse Events for Study OC5-DB-01 ...................................................... 69 
Table 9: Summary of Types of Adverse Events Experienced in OC5-DB-01 (Safety 
Analysis Set) .............................................................................................................. 71 
Table 10: Sample Size Calculation Primary Endpoint .................................................................. 76 
Table 11: Power Calculations for Change from Baseline in eGFR .............................................. 76 
2.2 List of Figures 
Figure 1: Effect of O. formigenes Treatment on Plasma Oxalate Levels in Patients with 
End-Stage Renal Disease Treated with O. formigenes Delivered as Frozen 
Cell Paste (OC2) ........................................................................................................ 28 
Figure 2: A Forest Plot of Difference in Change in Urinary Oxalate Excretion from 
Baseline to Week 8 of Treatment in Different Subgroups in the OC5-DB-01 
Study. ......................................................................................................................... 32 
Figure 3: Follow Up of Plasma Oxalate Levels in Patient 1 during Treatment with 
Oxalobacter formigenes ............................................................................................. 34 
Figure 4: Follow Up of Plasma Oxalate Levels in Patient 2 during Treatment with 
Oxalobacter formigenes ............................................................................................. 34 
Figure 5: Oxalate Degrading Activity of OC5 Compared to OC3 ................................................ 37 
Figure 6: Study Design for OC5-DB-02 Study ............................................................................. 44 
Figure 7: Illustration of Safety Reporting in the ePHex Study ..................................................... 45 

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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
 
Table 2: Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
AGT 
Alanine/glyoxylate aminotransferase 
AKI 
Acute Kidney Injury  
ALP 
Alkaline phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
BUN 
Blood Urea Nitrogen 
CAPD 
Continuous Ambulatory Peritoneal Dialysis 
CCPD 
Continuous Cycling Peritoneal Dialysis 
CFU 
Colony Forming Units 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
e/a 
Early to late ventricular filling velocity 
e/é 
Medial to lateral diastolic peak velocity 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of study 
EOT 
End of treatment 
ESRD 
End-Stage Renal Disease 
FAS 
Full Analysis Set 
FDD 
First Dose Date 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GRHPR 
Glyoxylate reductase / hydroxypyruvate reductase 
HD 
Haemodialysis 
HOGA 
4‑hydroxy‑2-oxoglutarate aldolase 
ICF 
Informed Consent Form 

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Abbreviation or Specialist Term 
Explanation 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
LDD 
Last Dose Date 
MAR 
Missing at random 
MCHC 
Mean Cell Haemoglobin Concentration  
MCV 
Mean Cell Volume 
MI 
Multiple Imputation 
MNAR 
Missing not at random 
MRMM 
Mixed-effect repeated measures model 
NLT 
Not Less Than 
NMT 
Not More Than 
OC2 
Old investigational Drug, evaluated in earlier clinical studies.  
OC3 
Old Investigational Drug, evaluated in earlier clinical studies. 
OC5 
Investigational Drug 
PH 
Primary Hyperoxaluria 
PI 
Principal Investigator 
The investigator who leads the study conduct at an individual 
study centre.   
PMM 
Pattern-mixture model 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
STE 
Speckle Tracking Echocardiography 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WBC 
White Blood Cell Count 
 
 

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4 INTRODUCTION 
4.1 Primary Hyperoxaluria 
4.1.1 Aetiology, Clinical Features and Epidemiology 
Primary hyperoxaluria (PH) type I, II and III are rare autosomal recessive inborn errors of 
glyoxylate metabolism. PH type I is caused by deficient or absent activity of liver specific 
peroxisomal alanine/glyoxylate aminotransferase (AGT). In some patients with PH type I, enzyme 
is present but mis-targeted to mitochondria where it is metabolically inactive. PH type II occurs as 
a result of deficient glyoxylate reductase-hydroxypyruvate reductase (GRHPR) enzyme activity. 
Oxalate overproduction in patients with PH type III is caused by loss-of-function of the 
mitochondrial 4‑hydroxy‑2-oxoglutarate aldolase (HOGA) enzyme (Cochat and Rumsby, 2013). 
All types of PH are characterized by severe hyperoxaluria and hyperoxalemia. Oxalate cannot be 
metabolized by human cells and is eliminated through the intestines and the kidneys as an end 
product of metabolism. Oxalate is freely filtered at the glomerulus, reabsorbed in proximal tubules 
and secreted by the distal tubules. Urinary oxalate excretion levels in PH patients are extremely 
high (>1.0 mmol/day/1.73m2) as compared to normal levels (< 0.5 mmol/day). Oxalate precipitates 
with calcium at µmolar concentrations, and high oxalate concentration levels damage the renal 
parenchymal cells both as free oxalate and as calcium-oxalate crystals (Cochat and Rumsby, 2013). 
In addition to calcium-oxalate deposition, chronic hyperoxaluria and calcium oxalate crystals are 
associated with parenchymal inflammation and interstitial fibrosis (Cochat and Rumsby, 2013; 
Hoppe et al., 2009). 
In PH, marked hyperoxaluria is present from birth. There is however a marked interfamilial as well 
as intrafamilial heterogeneity of disease expression. The individual hepatic oxalate production and 
time for exposure to high oxalate (age) are important factors for progression of the disease (Zhao 
et al., 2016). The majority of patients are symptomatic during childhood and in most cases before 
10 years of age. Some patients suffer from the severe infantile oxalosis and reach end-stage renal 
disease (ESRD) before one year of age. In some cases, however, the disease may go unrecognized 
until patients reach 30-50 years of age. Overall, approximately 30% of PH patients have reached 
ESRD by age of 15 (Rare Kidney Stone Consortium, 2013). Untreated, PH1 leads to death in 
most patients, but even with currently available treatments average life expectancy is shorter than 
in the general population (Cochat et al., 1995; Hoppe et al., 2009; Van der Hoeven et al., 2012).  
PH is an ultra-rare disease with a prevalence for PH type I of 1-3 per million and an incidence rate 
of approximately 1 per 120 000 births in Europe. PH type I is the most severe and the most common 
variant, accounting for 70-80% of all known cases. Available prevalence and incidence rates may 
however be underestimated because of the diagnosis being delayed or overlooked (Cochat and 
Rumsby, 2013). Early diagnosis, molecular subtyping and prompt initiation of conservative 
treatment are of vital importance for PH patients. 
The clinical hallmark of the disease is recurrent calcium-oxalate urolithiasis and/or 
nephrocalcinosis with progressive decline in renal function. PH type 1 patients with ESRD receive 
dialysis while waiting for combined liver and kidney transplantation. So far dialysis has not been 
shown to overcome the problems caused by ongoing oxalate production and deposition at extra-
renal sites. Even the most intensified dialysis regimen is not able to cope with the increasing 
oxalosis that often leads to multiple organ dysfunction including ischemic ulcers of the skin, 

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metabolic bone disease, refractory anaemia, cardiomyopathy and cardiac conduction system 
abnormalities causing severe morbidity and mortality (Cochat and Rumsby, 2013; Hoppe, 2012).  
PH type 2 is a less severe disease, and these patients reach ESRD later in life, around age 40-50 
years. PH type 3 is the mildest form of the disease with severe recurrent kidney stones, but as of 
today no known patients with ESRD. 
4.1.2 Unmet Medical Need 
PH is a seriously debilitating and life-threatening disease with a high unmet medical need. There 
is currently no approved pharmaceutical therapy for PH available on the market. Eventually the 
only curative therapy for PH type 1 is a combined kidney and liver transplantation at ESRD. For 
type 2 and 3, recurrent kidney transplantation is the only temporary treatment. 
A medical treatment, which can enhance or contribute to the removal of oxalate could be of 
immense importance in management of these patients. 
4.2 Oxabact 
The active study drug Oxabact consists of lyophilized Oxalobacter formigenes strain HC-1 in an 
enteric-coated capsule for oral administration. Oxabact comprises O. formigenes derived from a 
human strain HC-1. 
O. formigenes is a strict anaerobe that relies exclusively on oxalate as a substrate to obtain energy 
for its survival and growth. Three proteins involved in oxalate degradation have been purified, their 
genes isolated and expressed to understand the physiological significance of this bacterium 
(Stewart et al., 2004). It is currently believed to be the most efficient oxalate degrading enzymatic 
system that operates at neutral pH. O. formigenes is a part of the normal intestinal flora in humans; 
it is non-pathogenic and has never been isolated systemically as a pathogen. O. formigenes is also 
hypothesized to interact with the oxalate transporter proteins in the intestinal wall enhancing the 
transport of oxalate from plasma to the intestinal lumen. 
4.3 Oxabact Treatment for PH Patients 
Oxalobacter formigenes, given orally, has the potential to modify the course of PH by enhancing 
enteric elimination of oxalate (transfer of oxalate from plasma to the intestine), thereby potentially 
mobilizing the oxalate stores and decreasing total body burden and serum levels of oxalate.  This 
then could have significant benefit on the heart, the joints and the kidney, especially on the tubular 
function, as well as other affected organs such as skin, skeleton and eyes. 
Although kidneys are believed to be the principal route for oxalate excretion, considerable 
intestinal excretion of oxalate has been shown in animal models. Colonic secretion of oxalate is an 
extra-renal route for oxalate elimination in rats with hyperoxalemia with or without chronic renal 
failure, which is also a clinical feature seen in patients with Primary Hyperoxaluria (Hatch and 
Freel, 2005). Administration of the bacteria O. formigenes is proven to create a trans-epithelial 
gradient for oxalate flux from the blood stream over to the small intestines, to increase degradation 
of oxalate in the gastrointestinal tract, thus promoting enteric elimination of oxalate. The bacteria 
have also been shown to actively promote enteric elimination of oxalate through its secretion of a 
signal to epithelial cells to transport oxalate from plasma to intestines in animal models (Hatch et 
al., 2011) 

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Incremental secretion of oxalate into the gut can also be maintained by constantly degrading the 
secreted oxalate with the help of O. formigenes in the gastrointestinal (GI) tract. Thus 
O. formigenes treatment is a potential therapy to promote the removal of endogenously produced 
plasma oxalate by enteric elimination, thereby lowering the body burden of oxalate in PH patients. 
It is also possible, that O. formigenes, can act to dissolve and remove oxalate deposits in the body. 
By enhancing transport of free oxalate from plasma to the gastrointestinal tract, O. formigenes can 
shift the equilibrium between solid and free oxalate in plasma and start a dissolution process, 
thereby releasing free oxalate from systemic deposits. In the long-term this will reduce systemic 
and tubular deposits in the patients and should result in a significant clinical benefit for all patients 
in all affected organs and tissues. 
4.4 Clinical Experience with Oxabact 
Five clinical studies in PH have been performed with older Oxabact products (OC2 and OC3): two 
phase I/II studies and two phase II/III studies, plus an open-label extension study following the first 
phase II/III study, see Table 3.  
In addition, a recent placebo-controlled, double blind randomized Phase I/II study (OC5-DB-01: 
EudraCT No. 2012-005606-22) has been performed with the new OC5 product in 8 clinical sites 
in Europe. This study enrolled 28 PH patients with maintained renal function and evaluated the 
efficacy and safety of Oxabact OC5 to reduce urinary oxalate and plasma oxalate in patients with 
PH. OC5-DB-01 started in December 2013 and the study ended in Jan 2015.  
An open-label phase II study with OC5 (OC5-OL-01, EudraCT No. 2013- 004368-74) to evaluate 
the efficacy and safety of Oxabact (OC5) to reduce plasma oxalate levels in patients who are on 
dialysis was completed in January 2020, see further Table 3. 
 

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Table 3: Summary of Clinical Studies 
Study 
Sites/Subjects 
Study Drug 
Treatment Time 
Outcome 
CTIxOC.002  
Phase I/II, open-label, non-
comparative 
– 
Single site, n=9 
– 
PH type I 
– 
5 males, 4 females 
– 
Mean age 14, range 3-49 
OC2: Oxalobacter formigenes frozen 
cell paste, containing 1000 mg (NLT 
1E+10 CFU), given orally b.i.d. with 
meals.  
4 weeks  
– 
Reduction in plasma oxalate in 
some subjects on dialysis 
– 
No safety concerns 
CTIxOC.002 A 2-3  
Phase I/II, open-label, non-
comparative 
– 
Single site, n=9 
– 
PH type I 
– 
5 males, 4 females 
– 
Mean age 16, range 5-50 
OC3a*: Enteric coated capsule, 
containing 137 mg (NLT 1E+07 CFU) 
of lyophilized powder. 
One capsule was given orally b.i.d. with 
meals. 
4 weeks  
– 
Significant reduction in urinary 
oxalate in nearly all subjects 
– 
No safety concerns 
OC3-DB-01  
Phase II/III, double-blind, 
placebo-controlled, multi-
centre 
– 
9 sites, n=42 
– 
PH type 1/2 
– 
19 males, 23 females 
– 
Mean age 13, range 6-39 
OC3b**: Enteric coated capsule, 
containing 137 mg (NLT 1E+07 CFU) 
of lyophilized powder. 
One capsule was given orally b.i.d. with 
meals. 
24 weeks 
– 
Post hoc analyses showed trends 
toward reduction in urinary 
oxalate 
– 
No safety concerns 
– 
Questionable 24-hour urine 
collections 
OC3-OL-01 
Phase II/III, open-label, non-
comparative 
– 
8 sites, n=37 
– 
PH type 1/2 
– 
16 males, 21 females 
– 
Mean age 14, range 6-38 
OC3b**: Enteric coated HPMC 
capsule, containing 137 mg (NLT 
1E+07 CFU) of lyophilized powder. 
One capsule was given orally b.i.d. with 
meals. 
12-24 weeks 
– 
No trends towards reduction in 
urinary oxalate 
– 
No safety concerns 
– 
Questionable 24-hour urine 
collections 
OC3-DB-02  
Phase II/III, double-blind, 
placebo-controlled, multi-
centre 
– 
3 sites, n=36 
– 
PH type 1/2 
– 
17 males, 17 females 
– 
Mean age 22, range 3-62 
OC3b buffer**: Buffer formulation, 
containing 500 mg (NLT 1E+07 CFU) 
of lyophilized powder. 
Reconstituted with bicarbonate buffer, 
given orally b.i.d. before meals. 
24 weeks 
– 
No trends towards reduction in 
urinary oxalate 
– 
No safety concerns 
– 
Improved 24-hour urine 
collections 

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Study 
Sites/Subjects 
Study Drug 
Treatment Time 
Outcome 
OC5-DB-01  
Phase I/II, double-blind, 
placebo-controlled, multi-
centre 
– 
8 sites, n=28 
– 
PH type 1 / 2 / 3 
– 
15 males, 13 females 
– 
Mean age 14.5, range 3-27 
OC5#: Enteric coated gelatin capsule, 
containing 80 mg (NLT 1E+09 CFU) of 
lyophilized powder. 
One capsule was given orally b.i.d. with 
meals. 
8-10 weeks 
– 
No significant difference for 
primary endpoint (urinary oxalate 
excretion) 
– 
Marked patient heterogenity with 
indication that oxalate deposits 
may be dissolving in OC5-treated 
subjects 
– 
Post hoc analyses identified 
significant differences in some 
parameters including kidney 
function markers 
– 
No safety concerns 
OC5-OL-01  
Phase I/II, open-label, non-
comparative, multi-centre 
– 
3 sites  
– 
12 PH patients with ESRD 
treated with dialysis 
enrolled; 8 subjects entered 
continued treatment phase 
OC5#: Enteric coated gelatin capsule, 
containing 80 mg (NLT 1E+09 CFU) of 
lyophilized powder. 
One capsule was given orally b.i.d. with 
meals. 
6 weeks +36 
months  
– 
Study started in May 2014 and 
ended in January 2020.  
– 
12 subjects received study drug; 
8 subjects entered the continued 
treatment period. 6 subjects 
completed 12 months, 5 subjects 
completed 24 months and 3 
subjects completed 36 months of 
continued treatment.  
MRMM analysis showed 
decreased total plasma oxalate 
levels over time and there were 
signs of improved or stabilised 
myocardial function in subjects 
who have received continued 
treatment. 
*OC3a:  
OC3 active ingredient prior to technology transfer and scale-up 
**OC3b: OC3 active ingredient after technology transfer and scale-up 
#OC5: OC5 active ingredient after process development and transfer 
 

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4.4.1 Clinical Experience in PH Patients  
 
4.4.1.1 CTIx.002 
The first phase I/II study (CTIx.0002) was conducted in 9 subjects using a frozen cell paste 
formulation of O. formigenes (OC2). Subjects were given two doses of OC2 per day for four 
weeks. Six subjects with serum creatinine <1 mg/dL (inclusion criteria) and three PH I patients 
in ESRD who were undergoing dialysis were included in this study (Hoppe et al., 2006). 
This study showed that NLT 1E+10 CFU administered twice a day for 4 weeks resulted in a 
20% (range 6-43%) reduction in 24-hour urinary oxalate excretion in six subjects with 
measureable urine (p=0.0313, Wilcoxon rank-sum test). Overall, the median reduction in 
plasma oxalate levels was 47% (p=0.0195). The decrease in plasma oxalate was substantial 
(>30 μmol/L) in 2 of the 3 subjects with end-stage renal disease. OC2 treatment was well 
tolerated in all subjects in the study. 
Figure 1 shows the change in plasma oxalate in the subjects in ESRD. Pre-dialysis plasma 
oxalate measurements were made once a week. A substantial decrease in plasma oxalate was 
observed in two of the subjects in ESRD and no safety concerns were observed (Hoppe et al., 
2006). In one of the subjects (Female 21 years on HD) the treatment was prolonged to 5 weeks 
since the therapeutic effect was quite significant and this subject also reported amelioration of 
clinical symptoms under therapy with less pain due to oxalate osteopathy. 
Figure 1: Effect of O. formigenes Treatment on Plasma Oxalate Levels in Subjects with 
End-Stage Renal Disease Treated with O. formigenes Delivered as Frozen Cell Paste 
(OC2) 
 
Note: The eight year-old male did not take all study medication per protocol after second week of treatment. 
HD=Haemodialysis, CCPD=Continuous Cycling Peritoneal Dialysis; CAPD=Chronic Ambulatory Peritoneal 
Dialysis. 
 
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4.4.1.2 CTIx.002 Amendments 2 and 3 
The second phase I/II study was a single arm, single centre study conducted under an 
amendment of the same protocol (CTIx.002 A2-3) and enrolled 9 subjects. In this study, O. 
formigenes was lyophilized and administered as an enteric-coated capsule (OC3a active 
ingredient). The dose was NLT 1E+07 CFU given twice a day for 4 weeks. In eight subjects 
with measureable urine, there was a reduction in 24-hour urinary oxalate excretion by a median 
58% (p=0.0078, Wilcoxon rank-sum test), ranging from 4% to 95%. Plasma oxalate decreased 
overall by a median 26% and the reduction ranged from 22% to 84% in 6 of these subjects. 
The plasma oxalate decreased by 26 μmol/L in the subjects with end-stage renal disease. OC3a 
treatment was well tolerated.  
4.4.1.3 OC3-DB-01 
Based upon results from the phase I/II studies, OxThera transferred and scaled up the 
manufacturing of OC3 (OC3b active ingredient). The third study was a phase II/III randomized, 
double blind, placebo-controlled study that investigated the safety and efficacy of lyophilized 
O. formigenes administered as an enteric-coated capsule. In contrast to the preceding single 
center studies, this study was conducted at 9 sites in France, the Netherlands, United Kingdom, 
Germany, and the United States. Of the 42 subjects enrolled, 19 were randomized to receive 
NLT 1E+07 CFU OC3b and 23 to placebo. Study drug was administered twice daily for 
24 weeks. It should be noted that this study was the first large international study to evaluate a 
new therapy in subjects with PH in a randomized and placebo-controlled fashion.  
Analysis of the prospectively defined primary endpoint change in urinary oxalate excretion 
showed no difference between the OC3b and placebo treatment groups on percentage change 
from baseline to Week 24 in urinary oxalate excretion. No treatment effect was seen in analyses 
of secondary endpoints.  
In an attempt to understand the lack of treatment effect in this larger study, an independent 
expert committee of clinicians was tasked to review the adequacy of the 24-hour urine data. 
They determined that despite the detailed instructions provided to the sites, the sites varied in 
quality of the urine collection, handling and shipping. Also, some subjects had a large amount 
of variability in their 24-hour urinary creatinine measurements across collections in the study 
indicating poor compliance. After the data review, the expert committee established stricter 
eligibility criteria for valid urine samples, and developed rules for post hoc analyses.  
Results from the post hoc analyses showed that the mean percentage change in urinary oxalate 
to creatinine ratio (mmol/mol) was -21% (SD=23%) in subjects given OC3b and -7% 
(SD=21%) in placebo, a difference of -14% (p=0.056, Student’s t-test). Analysis of data from 
the two largest sites (n=20), showed a mean percentage change of -37% (SD=17%) from 
baseline in subjects treated with OC3b and -9% (SD=22%) in subjects treated with placebo, 
corresponding to a difference of -28% (p=0.006). These two sites were also the most 
experienced in the conduct of clinical studies in this patient group.  
OC3b was safe and well tolerated with a similar distribution of adverse events (AE) in the 
active treatment and placebo groups. The most commonly reported individual AE were 
headache, nausea and vomiting. 
4.4.1.4 OC3-OL-01 
This was an open-label extension, single-arm, 6-month study evaluating the safety of OC3b 
with long term exposure in subjects who had completed participation in the double-blind, 
placebo-controlled efficacy study (OC3-DB-01). Subjects with less than 20% reduction in 

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urinary oxalate levels at week 12 compared to time of screening in the OC3-DB-01 study (i.e., 
at entry into the qualifying study OC3-DB-01) were withdrawn from the study. 
A greater proportion of subjects who received placebo in the OC3-DB-01 study [13 (65.0%)] 
experienced a stone event (renal stones and/or signs and symptoms of renal stones) compared 
with those who had received OC3b [5 (31.3%)]. The mean incidence of stone events, adjusted 
for a 48-week study period, was 0.46 (SD: 0.89) and 0.84 (SD: 1.00) in subjects who had 
previously received treatment with OC3 or placebo respectively. The validity of these 
differences should however be considered due to the inherent difficulties in defining a “new” 
stone event in this subject population, the relatively short follow-up time and varying time of 
exposure to study drug. 
Overall, estimated glomerular filtration rate (eGFR) did not change during the study. Similar 
results were seen in subjects with Stage II and Stage III chronic kidney disease. Changes in 
this parameter were not expected during this relatively short follow-up. 
Overall, there were no clinically relevant changes in free plasma oxalate during the study. 
The majority of subjects [24 (85.7%) subjects] did not show a ≥20% reduction in urinary 
oxalate to creatinine ratio during this open-label (OL) study (i.e. did not meet responder 
criteria). Among the seven subjects that were given OC3 for 48 weeks (DB and OL study 
combined) the mean reduction in urinary oxalate was 24%. At the end of study, 2 of these 
subjects were non-responders and 5 remained responders. The corresponding reduction in 
urinary oxalate among the seven subjects, who received placebo for 24 weeks during the DB 
study followed by 24 weeks of OC3b treatment in this OL study, was 23%; however, the 
reduction during the preceding 24 weeks of placebo treatment was 19% for this subgroup of 
subjects. Three of these subjects had an additional reduction of ≥20% during the OL study 
alone. 
Overall, OC3b was safe and well tolerated in the OL extension study with no unexpected safety 
issues raised and the adverse events reported were essentially evenly distributed between 
subjects who had previously received OC3 treatment compared with those who had received 
placebo in terms of severity, seriousness and relationship. 
4.4.1.5 OC3-DB-02 
In phase II/III OC3-DB-02 the study medication was administered as OC3b lyophilized powder 
suspended in water together with a bicarbonate buffer (OC3b buffer), and administered 
concomitantly with 10-20 mg esomeprazole (Nexium granules) taken with water once daily. 
The reason for using a buffer formulation was to increase the dose administrated, to have an 
earlier release of the bacteria in the GI tract, and to reduce the time to recovery of lyophilized 
bacteria.  
The primary efficacy analysis showed no reduction in urinary oxalate excretion following 
treatment with OC3 for 24 weeks compared to placebo. Both treatments showed a slight 
decrease in the urinary oxalate compared to baseline. The reduction of the urinary oxalate was 
analyzed in several subsets of subjects, including subject populations based on disease 
characteristics, age and region. Decreases in urine oxalate were seen in the OC3b group as well 
as in the placebo group. A significant treatment difference in favor of OC3b treatment was not 
found. OC3b treatment showed no effect on the overall proportion of responders following 
24 weeks of treatment. The percentage responders in the OC3 and placebo group was 25% 
(5/20) and 42% (5/12), respectively.  

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Overall, the day-to-day variability of urinary oxalate and creatinine measurements was much 
improved in this study as compared to OC3-DB-01. Results were basically similar when 
looking at oxalate per creatinine ratio or oxalate 24-hour excretion, which indicates that the 
24-hour collections were of good quality. In addition to implementing urine acceptance criteria, 
the instructions to subjects and study personnel were much improved in this study. 
OC3 treatment did not result in a clinically significant reduction of the plasma oxalate levels, 
although the active group had a decrease in plasma oxalate concentration of -12% whereas the 
placebo group had an increase of 7%.  
OC3b was safe and well tolerated with an AE profile similar to the placebo. AE were most 
frequently reported in the placebo group. The most frequently reported AE were infections and 
gastrointestinal disorders. The majority of AEs were of mild or moderate intensity and 
considered by the investigator to be not related to the OC3 treatment. Overall, treatment with 
OC3 was safe and well tolerated. 
4.4.1.6 Phase I/II Study of OC5 (OC5-DB-01) 
The OC5-DB-01 study was a double-blind, randomized, placebo-controlled, multi-centre study 
to evaluate the efficacy and safety of Oxabact OC5 in PH patients with maintained renal 
function (i.e. eGFR or a creatinine clearance of ≥ 40 mL/min normalized to 1.73m2 body 
surface area). The subjects were randomized to treatment with Oxabact or placebo, and were 
administered one capsule twice a day for 8 - 10 weeks. Each dose of Oxabact corresponded to 
not less than 109 CFU O. formigenes and not less than 100 mmol/19 h of oxalate degrading 
capacity. The primary objective of the study was to evaluate the efficacy of Oxabact drug 
product to reduce urinary oxalate excretion following 8 - 10 weeks of treatment.  
In total, 44 subjects from 8 sites in Germany, France, and the United Kingdom were screened 
for inclusion in the study. 28 of these were randomized; 14 were randomized to receive Oxabact 
and 14 randomized to receive placebo. All 28 subjects fulfilled the FAS and Safety set criteria, 
received the treatment and completed the study. 
The primary analysis for the OC5-DB-01 study did not identify a statistically significant 
difference between the OC5 treatment and placebo in terms of its effect on urinary oxalate 
excretion. After 8 weeks’ treatment, the change in urinary oxalate excretion appeared slightly 
higher (0.182 mmol/24 h/1.73 m2) in the OC5 group than in the placebo group; this difference 
did not achieve statistical significance (p=0.22). OC5 treatment did lead to a statistically 
significant increase in the number of O. formigenes cells in the faeces of subjects compared 
with placebo (p=0.00023). In all other secondary and exploratory endpoints, no significant 
differences were observed between OC5 and placebo.  
Subgroup analysis of the primary endpoint based on baseline urinary oxalate excretion, 
baseline eGFR, age or concomitant use of vitamin B6 therapy did not reveal any statistically 
significant differences between the treatment groups, but the magnitude of the least square 
difference between OC5 and placebo was larger in the eGFR<90 ml/min/1.73 m2 subgroup 
than in the eGFR≥90 ml/min/1.73 m2 subgroup (0.356 vs 0.040 mmol/24 h/1.73 m2) and larger 
in the subgroup of subjects aged 18 years or older than in the subgroup of subjects younger 
than 18 years (0.480 vs 0.039 mmol/24 h/1.73 m2). A Forest plot of difference in change in 
urinary oxalate excretion from baseline to Week 8 of treatment in different subgroups is shown 
in the figure below (Figure 2). 

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Figure 2: A Forest Plot of Difference in Change in Urinary Oxalate Excretion from Baseline to 
Week 8 of Treatment in Different Subgroups in the OC5-DB-01 Study. 
 
The figure displays estimate and 95 percent confidence intervals (Full analysis set). 
 
Despite a stratification of the two treatment groups for urinary oxalate excretion (below or 
equal to/above 1.5 mmol/24 h/1.73 m2), the subjects in the OC5 group had a more pronounced 
reduction in renal function than the placebo subjects at baseline. Mean baseline eGFR was 
lower in the OC5 group than in the placebo group (97.5±38.7 versus 123.1±45.4 
mL/min/1.73 m2), and renal and urinary disorders were more common in the OC5 group 
(11 cases versus eight cases). Most notably, four subjects in the OC5 group had a history of 
chronic renal failure, whereas no subjects in the placebo group had been affected by this 
condition.   
There was a negative correlation between plasma oxalate and eGFR in the full population at 
baseline (r = -0.508, p< 0.007) indicating that plasma oxalate concentration gradually increases 
with a decreasing kidney function in PH patients.  
In light of the observed difference in renal function between the two groups, ad hoc analyses 
were conducted to investigate the relationship between efficacy parameters and indicators of 
renal health.  
An analysis of the change in urinary oxalate excretion per urinary creatinine excretion showed 
a small (+5.4 mg oxalate/g creatinine), but statistically significant increase of oxalate excretion 
in the active group versus placebo, p=0.023 (FAS). 
≥18 years
<18 years
≥90 mL/min/1.73 m2
<90 mL/min/1.73 m2
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>1.5 mmol/24 h/1.73 m2
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(mmol/24 h/1.73 m2)
Subject age 
Estimated glomerular 
filtration rate 
Vitamin B6 
therapy
Baseline urinary 
oxalate excretion 

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Significant correlations were observed between renal function and the effect of OC5 treatment 
on urinary oxalate concentration. Overall, the OC5-induced increase in urinary oxalate 
excretion was larger in subjects with reduced renal function. The analyses also demonstrated 
that plasma oxalate concentration decreased as the number of O. formigenes increased in the 
OC5 treated subjects, p=0.04 (at study week 10). 
These findings suggest that the bacteria metabolise free oxalate that originates from plasma, 
thereby supporting that enteric elimination of oxalate has occurred.  
It is hypothesized that this reduction in free plasma oxalate shifts the endogenous equilibrium 
between free plasma oxalate, plasma protein-associated oxalate and tissue-deposited oxalate 
and forces a dissolution of oxalate deposits in plasma-proteins, vessels and kidneys which in 
turn leads to increased excretion of urinary oxalate. An analogous relationship between plasma 
urate levels and solid urate dissolution has been observed in patients with gout, where a 
reduction of serum uric acid to normal levels resulted in disappearance of urate crystals from 
synovial fluid (Pascual and Sivera, 2007). Because oxalate deposits are expected to be more 
pronounced in patients with reduced renal function, this hypothesis also explains why the effect 
of OC5 treatment was greater in subjects with more advanced kidney disease. The study also 
showed a statistically significant decrease in urine output in the OC5-treated subjects which 
also suggest that O. formigenes confers some beneficial effect on water reabsorption and urine 
concentrating-ability in the renal tubules of these subjects. 
4.4.1.7 Phase II Study of OC5 (OC5-OL-01) 
The OC5-OL-01 study was a phase 2, open-label, multi-centre study to evaluate the efficacy 
and safety of Oxabact OC5 to reduce plasma oxalate in patients with primary hyperoxaluria 
who are on dialysis. Subjects were treated for 6 weeks with study drug, with 4 weeks of baseline 
measurements prior to initiation of study medication and 4 weeks of measurement after drug 
administration. In Germany, the protocol was amended to allow a 36-month treatment period 
after the first 14 weeks of the study and in France a 12-month treatment period was approved. 
The study started in May 2014 and ended in January 2020. 
Fourteen subjects were screened and 12 subjects were enrolled in the study and received study 
drug. Eight subjects entered the continued phase of the study. Six subjects completed 12 
months of treatment, 5 subjects completed 24 months of treatment and 3 subjects completed 
36 months of treatment. A Mixed-effect Repeated Measures Model (MRMM) analysis showed 
a statistically significant decline in total plasma oxalate through time. Results of traditional and 
Speckle-Tracking echocardiography (STE) indicated that cardiac function substantially 
improved in 2 subjects who had impaired cardiac function at baseline, was stable within the 
normal range in the other subjects, and did not deteriorate in any subjects. Importantly, these 
observations occurred in the absence of clinically significant changes to the dialysis regimen. 
The safety profile was overall favourable, even in this severely ill study population.    
4.4.1.8 Compassionate Use 
Oxabact has also been evaluated during compassionate use in two 11-month-old girls with 
infantile oxalosis and ESRD (see Figure 3 and Figure 4). They received OC3b (administered 
via a gastrostomy tube) twice a day up to 4 weeks during two treatment periods. Dialysis 
regimens were unchanged. Plasma oxalate levels decreased from >110 μmol/L before to 
72 μmol/L following treatment in patient 1, and from >90 to 69 μmol/L (first treatment period) 
and to 50 μmol/L (second treatment period) in patient 2 (Hoppe et al., 2011).  
 

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Figure 3: Follow Up of Plasma Oxalate Levels in Patient 1 during Treatment with Oxalobacter 
formigenes 
 
 
 
Figure 4: Follow Up of Plasma Oxalate Levels in Patient 2 during Treatment with Oxalobacter 
formigenes 
 
 
 
Compassionate use of OC3b (broken capsules, 137-276 mg, mixed with phosphate buffer, 
reconstituted with 50-100 mL water and administered via gastric tube) twice a day up to 8 
weeks have been evaluated in two other patients with infantile oxalosis at two other sites in the 
United States and the United Kingdom, without any reduction in plasma oxalate (unpublished 
data). It has recently been concluded that the buffer used for administration of drug was sub-
optimal for survival of O. formigenes. 
OC3b and OC3 buffer were well tolerated and no serious side effects were reported during 
compassionate use.  
OC5 has been provided under named patient use to a female patient with infantile oxalosis in 
Germany. She developed chronic kidney disease shortly after birth and was treated with daily 
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. 

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peritoneal and 3 times/week haemodialysis. Treatment with OC5 (in buffer solution) started in 
December 2017, when the child was 3 months old and continued for 22 months, until 2 weeks 
after the patient had undergone a successful combined liver-kidney transplantation. Plasma 
oxalate was approximately 130 μmol/L at initiation of OC5 treatment, and overall a 35 % was 
seen (to around 80 μmol/L) after 16 months of treatment. Nephrocalcinosis and macular oxalate 
deposits did not deteriorate, and the disease progression was slowed down during the treatment 
period. The OC5 treatment was well-tolerated and no related adverse events were reported. 
(Pape et al.; 2020). 
4.5 Rationale for Current Phase III Study 
4.5.1 Overall Objective 
The overall objective of this study is to evaluate the efficacy of long-term treatment with 
Oxabact in PH patients with maintained kidney function but with an eGFR below normal 
ranges (<90 ml/min/1.73 m2) at baseline and a total plasma oxalate concentration ≥ 10 μmol/L. 
A comprehensive review of the data from the completed OC5-DB-01 study revealed a clear 
difference between the OC5 and placebo groups, including some significant effects in kidney 
function for OC5 treated subjects. The study findings suggest that, as a result of O. formigenes 
metabolising GI oxalate and enhancing transport of plasma oxalate into the GI tract, systemic 
oxalate deposits in the body start to dissolve in the OC5 treated subjects. The O. formigenes 
mediated enteric elimination process would then shift the equilibrium between crystallized 
and/or protein-associated oxalate and free oxalate towards the free oxalate in plasma, thereby 
releasing free oxalate from plasma proteins and from systemic deposits in the body. 
Furthermore, a recent publication (Sivaguru et al, 2018) demonstrated that calcium oxalate 
stones undergo multiple events of dissolution as they crystallise and grow within the kidney. 
Contrary to the perception that calcium oxalate stones do not dissolve, these findings would 
support the hypothesis of in vivo oxalate stone dissolution. 
When treated with Oxalobacter formigenes, subjects are expected to gradually deplete systemic 
oxalate deposits over time. The treatment duration needed for plasma oxalate levels to start to 
decrease would then depend on the amount of deposits at baseline for each individual subject. 
It is expected that 52 weeks treatment would be needed to see a treatment effect in this patient 
population.  
In blood, a large portion of the plasma oxalate is associated to proteins and a number of proteins 
such as albumin have been shown to interact with calcium oxalate during crystal formation 
(Hatch et al., 1977; Aggarwal et al., 2013). The intricate interplay between biological 
molecules and calcium oxalate crystals is an emerging research field, and may play a role in 
tissue deposit formation in blood vessels, in the heart and in the kidneys.  
Available study results from earlier Oxabact studies obtained to date also demonstrate that the 
patient population is extremely heterogeneous with subjects exhibiting high variability in their 
baseline characteristics and their stage of disease progression. Data shows that while kidney 
function is deteriorating in the subjects, plasma oxalate concentration and deposits in various 
organs are building up proportionally. In the recent OC5-DB-01 study there was a negative 
correlation between plasma oxalate and eGFR in the full population at baseline (r = -0.508, 
p< 0.007).  
In the previous double-blind multicentre study OC3-DB-02, there was a statistically significant 
difference in change in plasma oxalate between treated and placebo subjects in the group of 
subjects with a baseline eGFR <90 ml/min/1.73 m2 after 24 weeks of treatment with OC3.  

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The rationale for this study is, based on these findings, to prove that with a longer treatment 
time with the new, more potent OC5 product, there is a decrease in plasma oxalate 
concentration and calcium oxalate deposits over time in treated subjects. This outcome would 
prove the hypothesis that Oxabact is eliminating plasma oxalate via enteric elimination into the 
gut and is providing a clinical benefit by dissolution of calcium oxalate crystals.   
4.5.2 OC5 Development 
OxThera has made significant improvements in the Oxabact formulation to develop the new 
OC5 product. 
Process development has resulted in improvements of the culture conditions, cell harvesting 
procedures and optimization of excipients used for the freeze-drying process to develop the 
new highly concentrated product OC5.  As compared to OC3b, the OC5 product has hundred-
fold higher concentration of viable cells and these cells show a significantly higher recovery 
rate than OC3b.  
OC5 is derived from the same cGMP Master Cell Bank as the earlier product. However, the 
cell bank has been sub-cloned to meet stringent requirements with regard to viable cell count 
and oxalate degrading activity. Furthermore, culture conditions and harvest criteria in the 
fermentation process have been refined such that the cells are harvested at exponential phase 
rather than at the stationary phase. Together with optimized excipients and relative amounts of 
these and cells, the product is now also better protected in the lyophilization process. A higher 
number of viable cells recover from OC5 lyophilized powder than what was previously 
obtained from OC3b. 
In addition, product-related analytical methods have been refined since the previous production 
process. The viable cell count assay (CFU/g) has been improved to show the number of viable 
cells faster than previously. The oxalate degrading activity assay (moles oxalate degraded/g or 
CFU at 19h) has also been improved to measure activity at the recovered stage. One OC5 
capsule contains not less than 109 CFU and has the capacity to degrade not less than 100 mmol 
oxalate/capsule at 19h. 
The higher concentration of viable cells and higher oxalate degrading activity in OC5 allows 
for use of less lyophilized powder per dose. Thus, a smaller capsule, size 4 instead of size 2, is 
used for the OC5 product.  
OC5 is formulated as enteric-coated capsules designed to protect the O. formigenes bacteria 
from gastric juice and to deliver the active ingredient to its natural habitat and site of action, 
the small intestines. The disintegration time for the coated OC5 capsules is shortened in 
comparison to the OC3b capsules to better mimic the disintegration profile of a previous 
version of the product, OC3a capsules.  
As can be seen in Figure 5, the OC5 material begins replicating much quicker than does the 
OC3b material.  Hence, the new product shows superior activity. In essence, with an improved 
cell bank, improved harvesting technique and improved freeze-drying method, the quality of 
the product has been greatly improved.   

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Figure 5: Oxalate Degrading Activity of OC5 Compared to OC3 
 
4.5.3 Dose Justification 
Based on toxicity studies it is within the NOAEL to administer up to 9 x 1011 CFU of OC5 
twice daily to human subjects. The OC5-DB-02 study will administer a 109 CFU twice daily 
dose to all subjects. 
The oxalate degrading capacity of Oxabact is limited by the availability of endogenous oxalate. 
The typical daily production of endogenous oxalate is 4–7 mmol/1.73m2 in PH 1 patients. The 
optimal (i.e. in vitro) oxalate degrading capacity of the OC5 Oxabact capsules according to 
drug product specifications is approximately 15-25 times higher than the daily endogenous 
production of oxalate in PH patients (i.e. ≥100 mmol/capsule/19h). However, the amount of 
available oxalate cannot support this capacity. Since endogenous oxalate is limited, no safety 
concerns or difference in safety is anticipated with varying oxalate degrading capacity. 
It is necessary to provide an exaggerated dose of Oxabact to ensure continuous delivery of 
sufficient viable O. formigenes to the relevant part of the gastrointestinal tract. The bacteria 
need to survive transit through the stomach and upper small intestine and withstand the dilution 
effect from the normal gut microbiota. It is a competitive environment particularly given that 
O. formigenes are anaerobic and utilise only oxalate as an energy source. The dosing strategy 
supports the use of the same dose across age groups.
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4.6 Overall Risk and Benefit Assessment 
4.6.1 Burden 
Subjects will attend clinical visits at ten times throughout the study. This will involve time 
travelling to the hospital and the time required to see the investigator/study nurse. Blood 
samples will be collected during the clinical visits for safety laboratory evaluations and for 
plasma oxalate analysis. Approximately 20 mL of blood will be needed for the safety lab 
sample and approximately 5 mL for the plasma oxalate sample. Echocardiography will be 
performed four times during the study. Subjects will have an ultrasound of the kidneys taken 
two times during the study.  
Study medication will be administrated orally with breakfast and dinner as one capsule two 
times per day, for 52 weeks. The capsule size is quite small (size 4) and should be relatively 
easy to swallow even for younger subjects. The subjects will be asked to record the intake of 
the first and last dose of study drug in a diary. 
Subjects are requested to provide four faecal samples and six 24-hour urine samples during the 
study. Faecal and urine samples will be collected at subjects’ homes, a designated courier will 
pickup collections at times agreed with the subjects even during weekends if requested. 
Samples will be sent from the subject´s home directly to the central lab.  
4.6.2 Risk Threshold 
Detailed information on the anticipated adverse events of the OC5-DB-02 study is outlined in 
Section 11.5. In brief these potential risks may include: 
• Displacement of indigenous O. formigenes or changes in the normal gut microbiota 
• Infection risks 
• Elevated plasma formate 
• Gastrointestinal symptoms 
While the potential for these risks does exist, non-clinical and clinical data to date has not 
indicated that the Oxabact product is associated with any changes in the gut microbiota, local 
or systemic infection or elevated plasma formate levels. Previous studies with OC3 (OC3-DB-
01, OC3-DB-02) have also found that the OC3 product was safe and well tolerated with an 
adverse event profile similar to the placebo, even for gastrointestinal symptoms. While the 
OC5 product is more concentrated than the OC3 product, the safety profile has been shown to 
remain favourable, as supported by the pre-clinical and clinical studies to date.  
The bridging toxicology study (DP-1002), which included 28 consecutive days of twice daily 
oral administration by capsule of OC3 at 2 x 2E+08 CFU/day or OC5 at 2 x 9E+09 CFU/day 
to male and female rats was well tolerated with no test article-related changes or differences 
being noted between the two product formulations. The safety profile for OC5 was comparable 
to OC3, i.e. no changes observed on clinical observation, laboratory parameters, or 
histopathology considered specific to the treatment with OC5. 
Data collected to date for the completed OC5-DB-01 study and the current OC5-OL-01 study 
indicate that the OC5 product is safe and well tolerated. No related severe or serious adverse 
events have been reported so far in these ongoing studies for Oxabact, see Section 11.5. 
Analysis of potential change in microbiota due to treatment with OC5 during the OC5-DB-01 
study showed that no change in the microbiota could be detected during treatment with OC5.   
Overall, the safety data accrued to date would suggest that the OC5 drug product is safe and 
well tolerated and appears to have a similar safety profile as the earlier OC3 drug product.  

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In conclusion, the burden and risk threshold is deemed to be acceptable for the study and many 
efforts have been made to minimise burden and potential risks to the subjects. Furthermore, 
the subjects will visit the clinic ten times during the study for study specific visits in order to 
monitor adverse events and to make sure the subject is able to follow study procedures. 
4.6.3 Benefits 
PH is a devastating, life-threatening disease for which there are no approved pharmaceutical 
therapies available on the market. It is particularly emotive since it primarily affects a paediatric 
population. Consequently, there is a significant unmet medical need in treating this disease. 
Oral administration of Oxalobacter formigenes is a promising potential treatment for patients 
with PH. Clear beneficial effects of Oxalobacter formigenes have been demonstrated in animal 
models of PH and in earlier Phase I/II clinical studies. 
Based on analysis of the non-clinical and clinical safety data generated to date, Oxabact has  
been well tolerated. The older OC2 and OC3 Oxabact products have been given to more than 
80 subjects for time periods of 4 weeks to 12 months (with the majority of subjects having been 
treated for 6 months). In addition, the OC5 product has been administered to 14 subjects for 8-
10 weeks in the OC5-DB-01 study and for up to 36 months to 12 subjects in the ongoing OC5-
OL-01 study. Administration of O. formigenes as a frozen cell paste, capsule or buffered 
powder for suspension was well tolerated in subjects with Primary hyperoxaluria. No SUSARs 
have been reported in any of these studies for Oxabact, and Oxabact has had a favourable safety 
profile. 
The OC5-DB-02 study should provide valuable information on the ability of the improved OC5 
Oxabact product to reduce calcium oxalate deposits and eventually lower the level of plasma 
oxalate and confer clinical benefit in patients with PH. It will also generate further safety 
information on the product. The 52-week treatment time is expected to be enough to start to 
reduce the widespread oxalate deposits in the body and eventually also decrease plasma oxalate 
levels. 
4.6.4 Benefit: Risk Assessment 
There is an unmistaken need for additional therapeutic measures to treat patients with PH.  
These patients are at high risk for kidney damage due to over-production of oxalate and 
currently there are limited treatments available for this disease. The efficacy of Oxabact in PH 
patients is still to be proven.  
All non-clinical and clinical safety data to date indicate that Oxabact has been well tolerated. 
There have been no SUSARs for Oxabact reported in any clinical study with O. formigenes. 
Older studies with OC2 and OC3 drug product have been performed in over 80 subjects with 
treatment times of 4 weeks to 12 months. The 2 larger placebo-controlled studies (OC3-DB-
01 and OC3-DB-02) found that the OC3 product was safe and well tolerated with an adverse 
event profile similar to the placebo. Safety data from the completed blinded OC5-DB-01 study 
and the ongoing open-label OC5-OL-01 study suggest that OC5 has a favourable safety profile 
and would not be expected to differ from that of the earlier OC3 drug product. 
Thus, based on the knowledge with regard to the mechanism of action for OC5, a naturally 
occurring and non-pathogenic bacteria that relies exclusively on oxalate for its metabolism 
within the gut, and the available non-clinical and clinical data, the Sponsor believes that the 
benefit/risk evaluation of conducting this Phase III trial for treatment in patients with PH is 
considered favourable.  

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All in all, the potential clinical benefit to the target population (and study participants in this 
trial) is deemed to outweigh the potential risks implied and the study is therefore medically and 
ethically justifiable. 

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5 TRIAL OBJECTIVES AND PURPOSE 
5.1 Primary Objective 
o To evaluate the efficacy of Oxabact following 52 weeks treatment in patients with 
maintained kidney function but below the lower limit of the normal range (eGFR < 90 
ml/min/1.73 m2) and a total plasma oxalate concentration ≥ 10 μmol/L. 
5.2 Secondary Objectives 
o To obtain additional safety data from up to 52 weeks continuous treatment with 
Oxabact. 
5.3 Clinical Success Criteria for total plasma oxalate 
Oxabact will be considered associated with a clinically meaningful treatment effect on total 
plasma oxalate, if the results meet the following criteria:  
 
1. Statistically significant difference in change from baseline for total plasma oxalate 
concentration between Oxabact and placebo in favor of Oxabact after 52 weeks of 
treatment.  
AND 
2. Estimated difference of an absolute change from baseline for total plasma oxalate 
concentration between Oxabact and placebo of ≥5 µmol/L after 52 weeks of 
treatment.  
OR  
Estimated difference in percent change from baseline for total plasma oxalate 
concentration between Oxabact and placebo of ≥30% after 52 weeks of treatment.   
AND 
3. Greater percentage of subjects in the Oxabact arm than in the placebo arm achieving 
near-normalization of total plasma oxalate concentration (< 10 µmol/L) at least twice 
during weeks 24 to 52 of treatment.  
 
 
 
 

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6 INVESTIGATIONAL PLAN 
This study is a phase III, double-blind placebo-controlled, randomized, multi-centre study to 
evaluate the efficacy and safety of OC5 (O. formigenes) to stabilise/reduce plasma oxalate 
concentration, to stabilise/improve kidney function and to reduce oxalate deposits in PH 
patients. Enrolled subjects will have a maintained kidney function but below normal range 
(eGFR < 90 ml/min/1.73 m2) and a total plasma oxalate concentration ≥ 10 μmol/L. 
It is hypothesized that daily administration of O. formigenes facilitates the secretion of 
endogenously produced oxalate via the GI tract. The enteric elimination of oxalate may help 
to reduce the oxalate deposits and eventually decrease the plasma oxalate level. 
6.1 Background and Rationale 
A recent natural history study in PH patients included in the Rare Kidney Stone Consortium 
(RKSC) Registry (Zhao et al., 2016), studied the key determinants for renal outcome in this 
patient population. The patients included in the analysis had a mean eGFR of 
73 ml/min/1.73 m2. During a median follow-up of 3.9 years (1.0, 12.8), 20% of patients 
developed End-Stage-Renal-Disease (ESRD). The most important progression factors for 
kidney deterioration in patients with Primary hyperoxaluria (PH) from this registry study are 
detailed in Table 4. 
Table 4: Factors Univariately Associated with Incident ESRD among PH Patients without 
ESRD at Diagnosis 
Variable 
Hazard Ratio (95% CI) 
p-Value 
 
PH1 
13.17 (3.19-54.38) 
<0.001 
 
Age at diagnosis  
1.02 (1.00 to 1.04) 
0.02 
 
Uox, mmol/1.73 m2 per 24h 
1.13 (0.94 to 1.37) 
0.20 
Uox, mmol/1.73 m2 per 24h 
(Q4)* 
3.40 (1.40 to 7.90) 
0.01 
eGFR, ml/min per 1.73 m2 
0.96 (0.94 to 0.99) 
0.002 
 
*Q4: Quartile 4 related to a urinary oxalate excretion of > 1.87 mmol/1.73 m2 per 24hr 
 
Univariate analyses showed that the most important parameters governing the progression to 
ESRD in PH-patients were type of PH, highly elevated urinary oxalate excretion (the highest 
quartile Q4 with above 1.87 mmol/1.73 m2 per 24hr), age at diagnosis and eGFR at diagnosis.  
This protocol will include subjects with an eGFR below 90mL/min/1.73 m2 and a total plasma 
oxalate concentration of ≥ 10 μmol/L. The rationale for these inclusion criteria is based on 
available data from the previous studies with OC3 and OC5 and the above referenced analysis 
of registry data for PH patients. The following key points have been considered in determining 
the selection of subjects. 
• eGFR at diagnosis is statistically significantly inversely correlated to risk for ESRD 
(Zhao et al., 2016). The lower the eGFR, the higher the risk for progression to ESRD. 
In the selected patient population with an eGFR below 90 ml/min/1.73 m2 the natural 
disease progression is at a stage where a decline in kidney function (resulting in 
increased plasma oxalate) would be measurable over a 52-week study. The endpoints 
are selected to determine whether Oxabact treatment could halt or delay the disease 

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progression i.e. stabilise or reduce plasma oxalate and stabilise or improve kidney 
function over time. 
• The selected patient population would have increased levels of plasma oxalate at 
baseline, as a consequence of the declining eGFR, and thus it would be possible to study 
not only a stabilization, but also a decrease in plasma oxalate concentration during 52 
weeks treatment with Oxabact in these subjects.  
It is evident from current knowledge that baseline kidney function is an important factor 
determining the rate of disease progression and that there is a clear correlation between plasma 
oxalate concentration and kidney function. Consequently, it is important to harmonise the 
treatment groups considering these parameters.  
The following measures have been taken to prevent potential imbalances in the treatment arms: 
• Subjects with an eGFR below 90 ml/min per 1.73 m2 and plasma oxalate ≥ 10 µmol/L 
will be included in the study, in order to harmonise the study population with regard to 
stage of disease.  
• Subjects will be stratified at randomization firstly in an attempt to evenly distribute any 
PH type 2/type 3 patients and secondly to evenly distribute PH1 patients with a baseline 
Urinary oxalate (Uox) excretion more or less than 1.87 mmol/1.73m2 per day between 
the treatment groups. 
In order to further define the patient population, the endpoints will be analysed for sub-groups 
of subjects determined by the subject´s baseline oxalate excretion (urinary oxalate excretion 
more or less than (or equal to) 1.87 mmol/24hr/1.73m2), high and low age (greater (or equal 
to) or less than 18 years) and high and low eGFR (more (or equal to) or less than 60 
ml/min/1.73m2). Since these parameters seems to be the most important drivers of the disease 
progression, the subgroups of subjects with a high baseline urinary oxalate excretion, high age 
and a low baseline eGFR would be expected to show a more pronounced treatment response 
over 12 months.  
6.2 Overall Study Design and Plan 
The study subjects will be monitored for up to 8 weeks prior to initiation of study medication, 
in order to obtain a robust baseline for each subject. Subjects will be treated for 52 weeks with 
OC5 or placebo. After the treatment phase, subjects will be followed for safety for 2 weeks or 
until the day before first dose in the follow-up study OC5-OL-02, whichever occurs first.  
During the screening/baseline period, three visits in total will be done. Information on historical 
renal function (including eGFR, serum creatinine and the equation used to calculate historical 
eGFR) and kidney stone events (prior to informed consent) will be collected. For subjects under 
18 years of age and subjects that were <18 years up to 3 years prior to screening (i.e. for all 
subjects under 21 years at screening), height used to calculate historic eGFR will also be 
collected. 
The impact of stone events on days work/school attendance will be documented. During each 
of the screening/baseline visits, blood samples will be taken for safety labs, plasma oxalate and 
kidney function analyses. Subjects will have two Echocardiography examinations (Speckle 
Tracking and traditional echocardiography). Ultrasound of the kidney will be performed once 
during the baseline period. Subjects will be asked to provide one faecal and two 24-hour urine 
samples. These samples will be taken at the subject´s home. Subjects will be asked to complete 
a questionnaire evaluating their Quality of Life once during the baseline period.  

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Eligibility for plasma oxalate and eGFR will be based on the mean value of visit 1 and 2. 
For determination of eligibility, eGFR can be calculated using Schwartz or CKD-EPI equations 
that include serum creatinine and/or cystatin C. 
For the urinary oxalate excretion, a mean value will be determined for visit 1 and 2 
(screening/baseline period) and used for stratification/randomization. 
Following screening and baseline evaluations, eligible subjects will be randomized 1:1 to 
receive either OC5 or placebo twice daily for 52 weeks.  
During the treatment period, subjects will visit the clinic at weeks 8, 16, 24, 32, 40, 48 and 52. 
During these visits, blood sample for analyses of safety labs and plasma oxalate and kidney 
function will be taken and patient Quality of Life will be evaluated by a questionnaire during 
weeks 8, 24, 40 and 52. Speckle Tracking and traditional echocardiography will be done at two 
occasions during the treatment period, in weeks 24 and 48. Subjects will be asked to provide 
stool at three time points (weeks 24, 40 and 52) and 24-hour urine samples at four time points 
(weeks 8, 24, 40 and 52). Ultrasound of the kidney will be done at the end of the study in week 
48. Information on kidney stone events and related symptoms occurring between signature of 
the informed consent form and the end of study will be captured (Please see Figure 6 for details 
of the OC5-DB-02 study design).  
The subjects s will be offered to continue in an open-label follow-up protocol (OC5-OL-02, 
ePHex-OLE) with Oxabact treatment directly after the 52-weeks treatment period. A separate 
Clinical Trial Protocol and subsequent Clinical Trial Application will be issued for this study. 
Figure 6: Study Design for OC5-DB-02 Study 
 
 
 
Screening/ 
Baseline 
(up to 8 weeks) 
Treatment  
(52 weeks) 
Post-treatment 
safety  
follow-up 
(up to 2 weeks) 
Week 
-8-01 
0 
8 
16 
24 
32 
40 
48 
52 
 
Visit 
number 
1 
2 
3 
TS2 
4 
5 
6 
7 
8 
9 
10 
NA 
Plasma 
oxalate 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
eGFR3 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Stone 
events4,5 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Echocard.6 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
Safety labs7 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Stool 
X8 
 
 
 
X 
 
X 
 
X 
 
24h urine 
collection 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Ultrasound  
 
 
X 
 
 
 
 
 
 
X 
 
 
Quality of 
Life  
X8 
 
X 
 
X 
 
X 
 
X 
 
Adverse 
Events5 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
1All relevant assessments during screening/baseline will be completed during week -8 - 0, in total 2 visits will 
be done before baseline visit 3. The visits should be scheduled at least two weeks apart during the baseline 
period (visit 1, 2 and 3). After randomization of the subject, study drug will be ordered and shipped to the 
subject for start of treatment.   

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2Treatment Start (TS) - visit weeks in the treatment period will be calculated starting from treatment day one. 
3As determined by the Schwartz equation eGFR for children (age below 18), and CKD-EPI equation for adults 
(age 18 or above) based on serum creatinine. For determination of eligibility, eGFR can be calculated using 
Schwartz or CKD-EPI equations that include serum creatinine and/or cystatin C. 
4Kidney stone events and related symptoms will be captured at every visit, including occurrences in between 
visits. 
5A post-treatment safety follow-up will be performed as a telephone call (see Section 6.3.4 for details). 
6Two echocardiography examinations at least three weeks apart should be performed during the baseline period 
(week -8 – 0). The week 24 and 48 examination should be done within +/- 2 weeks of the clinic visit. If the 
images at week 24 and/or 48 do not meet quality criteria, the examination will be repeated within 4 weeks.  
7Safety labs will include blood and urine sampling. 
8Can be done anytime during screening/baseline, i.e. week -8 – 0. 
Safety evaluation will include physical examination, vital signs and safety labs at baseline and 
at weeks 8, 16, 24, 32, 40, 48 and 52. Adverse events will be monitored throughout the study.  
For the course of the study, the subjects should be instructed to maintain their normal diet and 
fluid intake as prescribed under their standard clinical care.  
Monitoring of adverse events, concomitant medication and compliance with the administration 
of study drug will be performed at least at each visit. Furthermore, questions on kidney stone 
events and related symptoms will also be asked throughout the study.  
After the intake of the last dose of study treatment (Last Dose Date; LDD), subjects will 
be followed for safety (see Section 6.3.4.1 for details on the post-treatment safety follow-up). 
The LDD is considered the End of Treatment (EOT); the end of the safety follow-up 
period is considered End of Study (EOS). Adverse events, including kidney stone events 
and related symptoms, are recorded throughout the entire treatment phase and safety follow-
up, i.e. until EOS (Figure 7); AE recording is described in detail in Section 11.4. 
Figure 7: Illustration of Safety Reporting in the ePHex Study 
First Dose Date 
(FDD) 
i 
Screening/Baseline 
Last Dose Date 
(LDD) 
i 
Treatment phase 
Safety follow-up 
t 
End of Treatment 
(EQT) 
I 
AEs reported in eCRF 
t 
End of Study 
(EOS) 
I 

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6.3 Schedule of Assessments 
The assessments to be performed during the study are described in Table 5, and the 
procedures are further described in Sections 6.3.1– 6.3.4. 
Table 5: Schedule of Assessments 
 
 
1. All relevant assessments during screening/baseline will be completed during week -8 - 0, in total 2 
visits will be done before baseline visit 3. The visits should be scheduled at least two weeks apart 
during the baseline period (visit 1, 2 and 3). After randomization of the subject, study drug will be 
Study period: 
Screening/Baseline1 
Week -8 - 0 
Treatment 
Week 0-522 
Post- 
treatment  
safety 
follow-up 
Week: 
 
 
 
0 
8 
16 
24 
32 
40 
48 
52 
 
Visit number3 
1 
2 
3 
TS 
4 
5 
6 
7 
8 
9 
10 
 
Incl/Excl criteria4 
X 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
PH Med History 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant med5 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (if 
appl) 
 
 
X 
 
 
 
 
 
 
 
X 
 
Plasma oxalate 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
eGFR6 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Stone events5,7 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs8 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Echocard. 
X9 
 
X9 
 
 
 
X10 
 
 
X10 
 
 
Ultrasound 
 
 
X 
 
 
 
 
 
 
X 
 
 
Stool 
X11 
 
 
 
X 
 
X 
 
X 
 
24 hr urine 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Review of Adverse 
Events5 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
X11 
 
X 
 
X 
 
X 
 
X 
 
Drug dispense/ 
Accountability12 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
II 
II 

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ordered and shipped to the subject for start of treatment. Treatment will start as soon as the first 
delivery of study drug to the subject has been done.  
2.
Treatment weeks will be planned from treatment day 1, i.e. visit week 8 will be scheduled at treatment 
day 1 + 56 days.
3.
Visit window during treatment period +/- 3 days (except for baseline period). In the case of an acute 
kidney injury occurring close to a scheduled visit, the visit will be rescheduled to ensure that the AKI 
does not adversely affect values (especially for eGFR).
4.
Eligibility criteria for plasma oxalate and eGFR samples taken at visit 1 and 2, will be evaluated 
during Baseline at visit 3. For determination of eligibility, eGFR can be calculated using Schwartz or 
CKD-EPI equations that include serum creatinine and/or cystatin C.
5.
A post-treatment safety follow-up will be performed as a telephone call (see Section 6.3.4 for details).
6.
As determined by the Schwartz equation for children (age below 18), and CKD-EPI equation for 
adults (age 18 or above). As detailed in point 4 above, eGFR equations including serum creatinine 
and/or cystatin C can be used for determination of eligibility.
7.
Kidney stone events and related symptoms will be captured at every visit, including occurrences in 
between visits.
8.
Safety labs include: haematology analysis, clinical chemistry analysis and urinalysis. FSH analysis for 
postmenopausal women will be done at screening.
9.
Two examinations to be done during week -8 – 0 at least three weeks apart.
10. Echocardiography to be done within +/- 2 weeks of the clinic visit at week 24 and 48. If the images 
fail quality criteria, the examination will be repeated within 4 weeks. Any repeat examination for the 
week 48 visit should be done before end of treatment at week 52.
11. Can be done anytime during screening/baseline, i.e. week -8 – 0.
12. First study drug dispense to subject will be arranged when enrollment in the study has been confirmed 
for the subject. During treatment period, study drug will be shipped to the subject every other week. 

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6.3.1 Screening 
Patient Information must be given and the Informed Consent form (ICF) must be signed prior 
to any study related procedures being performed. The investigator shall list all patients who are 
considered for participation in the study and who have signed the ICF on a Screening and 
Inclusion log. Pre-screening activities may be conducted if required. The inclusion and 
exclusion criteria should be reviewed. Demographics and baseline data will be collected.  
These include: 
• Date of birth, height, weight. 
• Physical examination and Vital Signs. 
• PH medical history (including diagnosis, renal function, kidney stone events). 
• Other relevant medical history, including concurrent illnesses and symptoms. 
• Prior/Concomitant medication and any non-medication therapy (e.g. physiotherapy) 
used in the 60 days prior to ICF signature. Any historical use of vitamin B6 and any 
other relevant medication, as judged by the investigator, should also be recorded.  
Subject demographic details collected will comply with local requirements regarding patient 
confidentiality in applicable countries. 
Historic renal function parameters (e.g. serum creatinine, eGFR including the equation used to 
calculate historic eGFR), if available, will be collected to determine the rate of renal function 
decline in years before participation in study OC5-DB-02. For subjects under 18 years of age 
and subjects that were <18 years up to 3 years prior to screening (i.e. all subjects under 21 years 
at screening), height used to calculate historic eGFR will also be collected. Information on 
historical stone events and related symptoms for the past 3 years will also be collected (visit 
1). The impact of stone events on days work/school attendance will be documented. 
A complete physical examination will be performed and will include assessment of: general 
appearance, gastrointestinal system, dermatological system, EENT (eyes, ear, nose, throat), 
head and neck, cardiovascular system, respiratory system, musculo-skeletal system, peripheral 
nervous system. Additional examinations may be done at the Investigators discretion.  
Vital signs assessed on study include temperature and blood pressure (systolic and diastolic), 
heart rate and respiratory rate assessed after 5 minutes resting in a supine position. Weight will 
be measured using a calibrated scale with the subject lightly clothed and shoes off. Height will 
be measured using a calibrated wall mounted stadiometer. Height should be measured at each 
visit for all subjects where the Schwartz equation is used to determine eGFR. This would apply 
to children (subjects under 18 years of age) and to any subject who turn 18 during the study 
period. For subjects who are adults at study start, height will only be recorded at screening.  
 
The following samples should be taken and sent for analysis: 
• Haematology analyses, clinical chemistry analyses, FSH analysis for post-menopausal 
women. 
• Urine sample for urinalysis.  
• Plasma sample. 
The subject (and parents when applicable) will be instructed how to collect 24-hour urine and 
faeces samples, and dates for collection will be scheduled. See Section 6.4 for further 

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information on collections at subject´s home. For the course of the study, the subject should be 
instructed to maintain their normal diet and fluid intake as prescribed under their standard 
clinical care. The subject will be asked to avoid taking ascorbic acid preparations or 
multivitamin preparations during the study period. The subject will be scheduled for an 
additional two visits during the baseline period.  
6.3.2 Baseline 
During the baseline period of up to 8 weeks, plasma oxalate sampling will be done at 3 
occasions (including the screening visit). The blood sample will be processed at the clinical 
site and the acidified plasma will be shipped frozen to the central laboratory (Academical 
Medical Center, Amsterdam, the Netherlands, AMC) for determination of total oxalate using 
the Isotope dilution Gas Chromatography with mass selective detection (GC-MSD). The mean 
of the two first plasma oxalate results (total plasma oxalate) during the baseline period will be 
reviewed for the eligibility criteria concerning plasma oxalate.  
For urinary oxalate excretion, a mean value will be determined for visit 1 and 2 
(screening/baseline period) and used for stratification/randomization. 
A separate sample will be processed at the site with ultrafiltration, acidification and sent frozen 
to AMC, to be analysed for free plasma oxalate concentration with GC-MSD. 
Plasma samples will also be sent to central laboratory BARC (BARC Europe, Ghent, Belgium 
for EU and Tunisia sites; and BARC USA, NY, USA for North-American sites) for analysis 
of serum creatinine for calculation of eGFR. Plasma samples will also be analysed for some of 
the exploratory analytes as specified in the lab manual.   
Patient Quality of Life will be evaluated using a questionnaire once during the baseline period.  
Safety labs will be taken at 3 occasions during baseline (including the screening visit) and 
analysed at central lab (BARC). Safety urinalysis will be analysed locally. Pregnancy test for 
women of childbearing potential will be done at visit 3 at central lab (BARC). Subjects will 
have two Echocardiography examinations done at visits 1 and 3. Ultrasound of the kidneys will 
be done once during baseline (visit 3). Information on kidney stone events and their impact on 
days work/school attendance will be collected during baseline (visit 2 and 3). Subjects will also 
be asked to provide two 24-hour urine samples and one faecal sample.  
The faeces sample will be collected at the subject´s home and shipped for analysis at Institut 
fur Mikroökologie, Herborn, Germany. The 24-hour urine sample will also be taken at the 
subject´s home and shipped to The Doctors Laboratory (TDL), London, United Kingdom.  
Any changes in concomitant medication will be recorded in the eCRF during the baseline 
period. At visit 3 each subject’s eligibility will be reviewed to assure that no exclusionary 
conditions have developed since the screening visit. The mean result from the two eGFR values 
(visit 1 and 2) calculated using the Schwartz/CKD-EPI equations based on creatinine and/or 
cystatin C will be reviewed for the eligibility criteria concerning eGFR at this point. If the 
eGFR values vary more than 50% between the two samplings, the subject will be evaluated for 
Acute Kidney Injury (AKI). If AKI is confirmed, the subject should not be randomized and 
needs to be stabilized first. When the kidney status is stable (as confirmed by routine local 
measurements/investigator decision), the subject may perform a new baseline period to verify 
eligibility. If eligible, the subject will be randomized. If the subject experiences another AKI 
during the baseline period, the subject should not be enrolled. A repeat baseline period may be 
performed only once.   

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For subjects who fail any of the inclusion or exclusion criteria, applicable parts of the eCRF 
should be completed (inclusion/exclusion criteria including corresponding data, and reason for 
the subject not being eligible). Subjects deemed not eligible for treatment should be recorded 
as screen failures on the Screening and Inclusion log. However, at the discretion of the 
investigator, a subject who fails screening may be re-evaluated (re-screened) at a later 
timepoint. 
After verification of the inclusion and exclusion criteria, the subject will be randomized and 
assigned a randomization number. Subjects will be randomized 1:1 to receive either OC5 or 
placebo twice daily for 52 weeks.  
At the clinical visit 3, the subject and/or the parents will be instructed about the administration 
procedures for the study drug. See Section 8 regarding treatment of subjects.  
After randomization of the subject, study drug will be ordered and shipped to the site. 
Treatment will start as soon as the first shipment of study drug has been delivered to the subject. 
The following visit dates, during the treatment period, will be calculated from the first day of 
treatment.  
6.3.3 Treatment Period 
During the 52-week treatment period, the subject will be followed by visits at week 8, 16, 24, 
32, 40, 48 and 52 according to Table 5. End of treatment (EOT) is defined as the day of last 
intake of study drug (Last dose date (LDD)). 
At the visits blood samples for determination of plasma oxalate, kidney function and safety 
labs will be taken. Subjects will have a physical examination and vital signs will be taken. 
Patient Quality of Life will be evaluated using a questionnaire at weeks 8, 24, 40 and 52.  
At week 24 and 48, Echocardiography (Speckle Tracking and traditional echocardiography) 
will be performed. Ultrasound of the kidneys will be performed at week 48.  
Subjects will be asked to provide four 24-hour urine samples, at weeks 8, 24, 40 and 52, and 
three faecal samples, at weeks 24, 40 and 52, during the treatment period. These collections 
will be done at the subject´s home and should be scheduled in connection with the visit (+/- 3 
days). The collections may be planned to occur during a weekend if preferred by the 
subject/parents. 
At each visit the subject will be assessed for the presence or absence of Adverse Events and 
any changes in concomitant medications. Information on the occurrence of any stone event and 
related symptoms will be collected at each visit (from the time of signed informed consent 
form until the end of the study). Days missed at school/work due to a stone event will also be 
documented. Information on stone events will be captured by completing the Adverse Event 
eCRF. (Please note this is a data entry convention and does not replace the per protocol 
definition of an Adverse Event as defined in Section 11.1.). 
Pregnancy test will be repeated at the last study visit for women of childbearing potential. 
The subject will receive shipment of study drug once every second week during the treatment 
period. Remaining study drug and empty containers will be returned to the clinic or site 
pharmacy continuously during the study at the clinic visits, as soon as new supply for the 
current treatment weeks has been received. The final return of study drug/empty containers 
will be done at the last clinic visit.  
In case an acute kidney injury/stone event should occur during the study treatment, the subject 
should be treated according to standard hospital care. The subject should not attend a visit if 

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they are experiencing an acute kidney injury/stone event since this may affect study values 
(particularly the eGFR value). When the event has been resolved the subject can be rescheduled 
to the study timetable.  
6.3.4 Follow Up   
The subject will be offered to continue in an open-label follow-up protocol (ePHex-OLE, OC5-
OL-02) with Oxabact treatment directly after the 52-week treatment period. A separate Clinical 
Trial Protocol has been developed and Clinical Trial Applications have been or will be 
submitted/approved for this study. 
6.3.4.1 Post-Treatment Safety Follow-Up 
Previous clinical experience with Oxabact® suggests that the bacteria only transiently colonise 
the gastrointestinal tract and faecal recovery generally drops below detectable levels 1-2 weeks 
after end of treatment (Hoppe et al. 2006). All subjects who complete study treatment in ePHex, 
withdraw or were withdrawn from the study prematurely, will be followed for safety. 
This post-treatment safety follow-up period starts the day after LDD in ePHex and ends:  
• Fourteen days after LDD in ePHex, or  
• The day before the first dose of study drug in the extension study ePHex-OLE has 
been taken, 
whichever occurs first.  
The follow-up will be performed as a telephone call maximum three working days after the 
end of the safety follow-up period. The subject will be asked for any AEs (incl. kidney stone 
events) appearing after completion of ePHex study treatment (i.e. after LDD). Additionally, 
any AEs that were present at the last completed study visit should be followed-up. Concomitant 
medication taken during the safety follow-up period should also be recorded.   
Adverse Drug Reactions, which are unresolved at the time of the safety follow-up call, should 
be followed by the Investigator until the event has resolved or, if persistent, has been assessed 
as “chronic” or “stable”. 
6.3.5 Electronic Patient Reported Outcome 
A web-based interface for electronic patient reported outcome (ePRO) will be used 
continuously during the study. Subjects will record details on collections of urine and faeces, 
Quality of Life as well as the first and last dose of study drug intake here. Subjects will regularly 
receive reminders to record this data, and to follow study procedures with study drug and 
specimen collection. 
6.4 Specimen Collection at Subjects’ Homes  
The collections of faeces and urine will be performed by the subjects in their home 
environment, and should be performed according to Table 5. The sponsor will provide 
collection kits and a Patient Handbook describing the collection procedures. Collection kits 
will either be taken home from the clinic by the subject or delivered to subject’s home by a 
courier. Pick-up of collections will be done by courier. 
6.5 Diet 
For the course of the study, the subjects will be instructed to maintain their normal diet and 
fluid intake as prescribed under their standard clinical care. They will be asked to avoid making 

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significant changes in their diet during the study specifically related to high oxalate foods and 
fluid intake.  
The subjects will be asked to refrain from ascorbic acid preparations or multivitamin 
preparations during the study. 
 
 

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7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 Subject Inclusion Criteria 
1. Signed informed consent (as applicable for the age of the subject).  
2. A diagnosis of PH (as determined by standard diagnostic methods).  
3. eGFR < 90 ml/min/1.73 m2. The Schwartz equation will be used to estimate GFR for 
children (age below 18), and CKD-EPI equation will be used for adults (age 18 or above). 
4. Plasma oxalate concentration ≥10 μmol/L in total plasma oxalate. 
5. Male or female subjects ≥ 2 years of age.  
6. Subjects receiving vitamin B6 must be receiving a stable dose for at least 3 months prior to 
screening and must not change the dose during the study. Subjects not receiving vitamin 
B6 at study entry must be willing to refrain from initiating pyridoxine during study 
participation. 
 
7.2 Subject Exclusion Criteria 
7. Inability to swallow size 4 capsules. 
8. Subjects that have undergone transplantation (solid organ or bone marrow).  
9. Subjects requiring dialysis or at immediate risk for kidney failure or in expected to be in 
need of dialysis during the study period.  
10. The existence of secondary hyperoxaluria, e.g. hyperoxaluria due to bariatric surgery or 
chronic gastrointestinal diseases such as cystic fibrosis, chronic inflammatory bowel 
disease and short-bowel syndrome. 
11. Use of antibiotics to which O. formigenes is sensitive. (This includes current antibiotic use, 
or antibiotics use within 14 days of initiating study medication.) 
12. Current treatment with a separate ascorbic acid preparation. 
13. Pregnant women (or women who are planning to become pregnant) or lactating women. 
14. Women of childbearing potential who are not using adequate contraceptive precautions.  
Please see Section 7.3 regarding requirements for contraception  
15. Presence of a medical condition that the Investigator considers likely to make the subject 
susceptible to adverse effect of study treatment or unable to follow study procedures, or 
any condition that is likely to interfere with the study drug mechanism of action (such as 
abnormal GI function).  
16. Participation in any interventional study of another investigational product, biologic, 
device, or other agent within 60 days prior to the first dose of OC5 or not willing to forego 
other forms of investigational treatment during this study. 
7.3 Contraceptive Precautions  
The following requirements should be followed for women of childbearing potential.  

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1. Females of childbearing potential will be included if they are either sexually inactive
(sexually abstinent for 14 days prior to the first dose continuing through 28 days after the
last dose), or using one of the following highly effective contraceptive methods (i.e. results
in <1% failure rate when used consistently and correctly) during this trial:
a.
intrauterine device (IUD);
b. surgical sterilization of the partner (vasectomy for 6 months minimum);
c.
combined (estrogen or progestogen containing) hormonal contraception associated
with the inhibition of ovulation (either oral, intravaginal, or transdermal);
d. progestogen only hormonal contraception associated with the inhibition of ovulation
(either oral, injectable, or implantable);
e.
intrauterine hormone releasing system (IUS);
f.
bilateral tubal occlusion.
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. In this trial abstinence is only acceptable if in line with the subjects preferred 
and usual lifestyle. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception.  As well, female condom and male condom 
should not be used together. 
2. Females of childbearing potential agree to remain sexually inactive or to keep the same
birth control method for at least 28 days following the last dose.
3. A female of non-childbearing potential must have undergone one of the following
sterilization procedures at least 6 months prior to the first dose:
a.
hysteroscopic sterilization;
b. bilateral tubal ligation or bilateral salpingectomy;
c.
hysterectomy;
d. bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle stimulating hormone (FSH) serum levels consistent with postmenopausal 
status.  
Since the study drug consist of commensal bacteria, which are a natural part of the microbiota, 
the risk of excretion via the semen or any negative effects from such excretion is highly 
unlikely. Therefore, no requirements for contraception is applied for male subjects.  
Females of childbearing potential will have a pregnancy test at baseline and at the end of the 
study at week 52. Additional information concerning participants becoming pregnant 
during the study can be found in Section 11.9. 
7.4 Subject Withdrawal Criteria 
If a subject fails to return for a scheduled study visit, the investigator will make a reasonable 
effort to contact the subject and determine why the subject failed to return and to schedule a 
new study visit.  Any information obtained during this contact will be documented in the study 
records.  

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A study subject will be discontinued from study treatment if: 
• Any clinically significant adverse event (AE), laboratory abnormality, illness, or 
other medical condition or situation occurs such that continued participation in the 
study would not be in the best interest of the subject. 
• OxThera or the Principal Investigator in consultation with OxThera may 
discontinue the subject at any time for medical and/or administrative reasons. 
• The Principal Investigator in consultation with OxThera may discontinue the 
subject in case there is a major protocol violation. 
• The subject requires dialysis. 
Any subject who withdraws prematurely from study treatment will be asked to complete all 
study assessments described for the week 48 and week 52 clinical visits (combined) and will 
be followed for safety for two weeks after the last intake of study drug. 
Subjects who withdraw consent from participating in the study at any time, will end the study. 
They will not have any further assessment and no further study data will be collected. 
For any subject who has withdrawn, the date of withdrawal and the reason for withdrawal from 
treatment and/or from the study will be recorded in the source data and eCRF. 
A subject who fails screening may be re-evaluated (re-screened) at a later timepoint. 
Withdrawn subjects should not be re-entered into the study. Subjects that are withdrawn due 
to major protocol violations will be summarized in the clinical study report. Additional subjects 
may be enrolled at the discretion of the Sponsor.  
 
 

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8 TREATMENT OF SUBJECTS 
8.1 Description of Study Treatment 
The study drug consists of OC5 as the active treatment and placebo with the same appearance. 
The study drug is supplied as enteric-coated capsules. One capsule shall be administered orally 
with water twice daily with breakfast and dinner. The study product is described in more 
detail in Section 9.  
8.2 Concomitant Medications 
Any medications including over-the-counter medications or herbal supplements will be 
recorded as concomitant drug therapy on the case report form. Prior/concomitant medication 
used in the 60 days prior to signing of the ICF will be recorded. Any historical use of vitamin 
B6 and any other relevant medication as judged by the investigator should also be recorded. 
Subjects will continue any medications they are receiving at study entry for underlying medical 
conditions and the medications will be recorded at screening and changes will be noted 
throughout the study, i.e. until EOS).  
8.2.1 Concomitant Treatment with Vitamin B6 
Subjects receiving vitamin B6 (pyridoxine) prior to study entry must be on a stable dose for at 
least 3 months prior to the screening visit. Subjects who are not receiving vitamin B6 at study 
entry will not be allowed to initiate vitamin B6 during study participation. Subjects will be 
encouraged not to change the dosing of vitamin B6 or discontinue vitamin B6 during study 
participation except for any safety events considered related to vitamin B6. 
8.2.2 Prohibited Medications 
Subjects are not allowed to receive any other investigational therapies during or within 60 days 
prior to study participation. 
Other prohibited medications are: 
-
Ascorbic acid preparations: Ascorbic acid preparations must not be used during the
study period (screening/baseline and treatment period) as it may affect the measurement
of urinary oxalate.
-
Long-term use of antibiotics: Subjects that require long-term use (more than 3
consecutive weeks) of antibiotics to which O. formigenes is sensitive during the
treatment period will discontinue study drug and be followed for safety.
-
For subjects that require short-term use of antibiotics during the treatment period, care
should be taken to primarily choose antibiotics to which O. formigenes is resistant. In
case of repeated short-term use (more than one course) an evaluation will be made to
assess the risk for interference with the study drug treatment.
o
O. formigenes has shown resistance to antibiotics that affect the cell envelope,
such as ceftizoxime, imipenem, ampicillin, amoxicillin and penicillin.
o
O. formigenes has shown sensitivity to antibiotics that are protein synthesis
inhibitors, such as chloramphenicol, doxycycline, erythromycin, and
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8.3 Treatment Compliance 
Subjects will be provided with a diary to record the intake of the first and last dose of study 
drug. Compliance to study treatment will also be checked with the subjects at each visit to the 
clinic. 
Unused medication will be returned to the clinic or site pharmacy at the next clinical visit, or 
the visit thereafter if new supply has not yet been received by the subject. Accountability will 
be done for the unused medication for an overall check of subject compliance. 
8.4 Randomization and Blinding 
At the screening visit, the subjects will be identified with a site-specific consecutive screening 
number consisting of site identification number and subject number. After completed screening 
procedures and eligibility check, the subjects will be assigned to blinded OC5 or placebo in a 
1:1 ratio according to a randomization list created by an independent statistician. The 
randomization list and treatment assignments will not be accessible until database-lock and 
unblinding. Subjects will be stratified, prior to randomization, firstly in an attempt to obtain an 
even distribution of PH type 2/type 3 patients and secondly to stratify the PH type 1 patients 
for a baseline urinary oxalate excretion above or below (or equal to) 1.87 mmol/24h/1.73 m2 
(based on the mean of the two first visits during screening).  
Randomization will be performed via a centralized procedure. 
If a subject discontinues the study, the subject number will not be re-used by another subject. 
Capsules with study medication will all have the same appearance to enable the double-blind 
study design.  
The following analytes/parameters on treatment, which may reveal a treatment-induced effect, 
will be defined as blind data and will remain blind to both subjects and sites until the study 
ends, the database is locked and the unblinding has occurred:  
• Plasma oxalate 
• Quantity of O. formigenes in faeces 
• Urinary oxalate and urinary calcium 
• Echocardiography (Speckle Tracking and traditional echocardiography) and 
ultrasound: During image analysis, Echocardiography and ultrasound central readers 
will also carry their assessments unaware of any clinical data from the study subjects. 
This data (except for quantity of O. formigenes in faeces) will also remain blind to the study 
team but may be subject to blind data quality review at the earliest at LPLV.  
 
 

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9 STUDY DRUG MATERIALS AND MANAGEMENT 
9.1 Study Drug 
OC5 is supplied as enteric-coated, size 4, gelatine capsules. One capsule contains NLT 1E+09 
CFU and has the capacity to metabolise not less than 100 mmol oxalate per 19 hours. Details 
on the product are described in Table 6 below. 
 
Table 6: Details of the Study Drug in the OC5-DB-02 Study 
Parameter 
High Dose 
Active Substance 
Lyophilized O. formigenes, strain HC-1 
Name 
Oxabact (OC5) 
Route of Administration 
Oral 
Dose form 
Enteric-coated capsule 
Viable cell count  
1.0 * 109 – 5.0 * 1010 CFU/dose  
Oxalate degrading capacity 
>100 mmol/capsule 
Excipients 
Oligofructose, maltodextrin, alginate, sucrose, 
microcrystalline cellulose 
9.2 Study Drug Packaging and Labelling 
Capsules will be filled into sealed aluminium tubes. Each tube will contain 18 capsules.  
The label, including subject number, will be placed on the aluminium tube and on secondary 
packaging (transparent bag) holding the aluminium tubes.  
The product will be labelled to meet national regulatory requirements. 
9.3 Study Drug Storage 
Study medication provided by the sponsor must be stored in a temperature-controlled freezer 
(-20°C +/- 5°C), in a locked area at site pharmacies before dispensing and delivery to subjects. 
Study medication should be stored refrigerated (2°C to 8°C) at the subject’s home, current 
stability data supports up to 4 weeks refrigerated storage.  
9.4 Study Drug Accountability, Handling and Disposal 
OxThera will supply study medication through the designated drug depot to all sites in the 
study. 
The drug depot will complete a drug inventory log to document receipt and distribution of 
study drug. They will send study drug to the site pharmacies as a controlled shipment at -20°C 
+/- 5°C. The site pharmacies will store study medication in a temperature- controlled freezer 
(-20°C +/- 5°C), in a locked area. The site pharmacies will distribute study drug to subjects and 
will inform subjects that study capsules should be stored refrigerated (2°C to 8°C) at their 
homes in the securely sealed tubes. Subjects will be supplied with sufficient capsules for dosing 
every second week. 
Unused study medication and empty vials will be returned to the clinic or site pharmacy at the 
next scheduled visit to the clinic after each delivery of new supply. The pharmacy will 

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document receipt of unused study medication. Any surplus of study medication will be 
reviewed and properly documented by the study monitor, and returned to the distributor. 
Investigational product accidentally destroyed in transit, in subject´s home or at the study site 
should be accounted for and documented.  

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10 ASSESSMENT OF EFFICACY 
The efficacy parameters to be assessed are: 
Primary Endpoint: 
 Change from baseline in total plasma oxalate concentration after 52 weeks of treatment.  
Key Secondary: 
 Change from baseline in kidney function after 52 weeks of treatment.  
 Frequency of kidney stones events after 52 weeks of treatment. Stone events are defined 
as:  
o Subject- or investigator reported symptoms, or  
o Stone passages or removals, or 
o Increase in number of stones assessed by ultrasound. 
Other Endpoints 
 Percent change from baseline in total plasma oxalate concentration after 52 weeks of 
treatment. 
 Subjects achieving ‘near-normalization’ of total plasma oxalate concentration (<10 
µmol/L) at least twice during weeks 24 to 52 of treatment.  
 Change from baseline in myocardial function as measured by Speckle Tracking and 
traditional echocardiography.  
 Change from baseline in free plasma oxalate concentration after 52 weeks of treatment. 
 Change from baseline in urinary oxalate excretion after 52 weeks of treatment.  
 Change from baseline in grade of nephrocalcinosis as assessed by Ultrasound 
 Change in number of O. formigenes in stool. 
 Association between change in number of O. formigenes in stool and change in total 
plasma oxalate concentration. 
 Change from baseline in score of Quality of Life questionnaire. 
 Change from baseline in markers for renal function, renal tubular capacity and 
inflammation:  
Urine: magnesium, phosphorus, citrate, calcium, glycolate, creatinine, urea, calcium 
oxalate 
crystals, 
pH, 
osmolality 
and 
urinary 
volume.  
Blood: magnesium, phosphorus, citrate, calcium, glycolate, BUN, ALP, bicarbonate, 
CRP, WBC, creatinine and cystatine C. 
10.1 Plasma Oxalate 
Samples for plasma oxalate will be collected during clinical visits, as specified in Table 5. The 
mean of the two values at Visit 1 and 2 will be the basis for eligibility criteria, whereas the 
mean of the three values obtained at Visit 1, 2 and 3 will be used as the mean baseline plasma 
oxalate value for statistical evaluation. 

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Samples for total plasma oxalate will be processed at the clinical site and analysed at Academic 
Medical Center, Amsterdam, the Netherlands (AMC). Each site will be provided with kits and 
supplies for collection, processing and shipping of blood samples for determination of total 
plasma oxalate. Complete instructions for the collection, processing, storage and shipping of 
sample will be provided in the site manual. 
Total plasma oxalate will be measured using isotope dilution gas chromatography with mass 
selective detection (GC-MSD). The measurement of plasma oxalate has analytical and 
biological variability. The analytical variability for the total plasma oxalate assay as performed 
by AMC is very low and the accuracy is within 1 µmol/L. The biological variability is higher 
and may be related to the actual hydration status for the subject. 
Ultrafiltered, acidified plasma samples will also be analysed for free plasma oxalate with GC-
MSD at AMC.  
The ratio between the two different results will be monitored throughout the study. 
Earlier studies on Oxabact used either an enzymatic assay for plasma oxalate where the oxalate 
available for enzymatic reaction is measured, or a standard plasma oxalate Ion 
Chromatography (IC) method where a 10 kDa ultra filtration step prior to acidification of the 
sample separates the protein-bound oxalate from the sample. Earlier study results should 
therefore be interpreted with this fact in mind. In contrast, since the sample preparation for 
analysis of total plasma oxalate does not include an ultra filtration step prior to acidification, 
the method measures the total amount of plasma oxalate. Since the major portion of the plasma 
oxalate is likely protein-associated (Hatch, 1990; Hatch et al., 1977) both ultrafiltered samples 
and samples without ultrafiltration will be analysed in the OC5-DB-02 study, complementary 
to each other. By using both sample preparation methods in the study for analysis of plasma 
oxalate, the ratio between the change in free plasma oxalate and the change in total plasma 
oxalate can be evaluated as an indicator of change in protein associated oxalate, as well as the 
two different parameters independently.  
A positive treatment effect on plasma oxalate would be a statistically significant difference in 
change from baseline in total plasma oxalate concentration after 52 weeks of treatment. The 
relationship between change in O. formigenes and change in total plasma oxalate will also be 
evaluated. 
Change from baseline in total plasma oxalate concentration after 52 weeks treatment will also 
be evaluated in the sub-groups of subjects with a urinary oxalate excretion above and below or 
equal to 1.87 mmol/L/24h/1.73 m2, age above or equal to and below 18 years of age and an 
eGFR above or equal to and below 60 ml/min/1.73 m2.  
10.2  Kidney Function Parameters 
Change from baseline in kidney function (eGFR) will be evaluated after 52 weeks treatment. 
The mean of the two values taken at visit 1 and 2 will be the basis for the eligibility criteria. 
For determination of eligibility eGFR will be evaluated using Schwartz or CKD-EPI equations 
that include serum creatinine and/or cystatin.  
Change in kidney function will be evaluated based on eGFR calculation using the 2009 
creatinine-based “Schwartz bedside” equation (for children below 18 years of age) (Schwartz 
et al., 2009) and 2009 creatinine-based CKD-EPI equation for adults (Levey et al., 
2009). Subjects who turn 18 during the study period will continuously be evaluated using the 
Schwartz equation, ie the equation used at baseline will be kept throughout the study.  

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Samples for eGFR calculations will be processed at the clinical site and analysed at central lab 
(Cerba Research [previously called BARC]). Each site will be provided with kits and supplies 
for collection, processing and shipping of blood samples for determination of serum creatinine 
and cystatine C. Complete instructions for the collection, processing, storage and shipping of 
sample will be provided in the site manual. 
10.3 Kidney Stone Events 
Kidney stones are hard deposits made of minerals and salts that form inside the kidneys. Most 
kidney stones (approximately 80%) are calcium stones, usually in the form of calcium 
oxalate. Stones can also be composed of struvite, uric acid or cystine. Stones vary in size and 
shape, ranging from a few mms up to 40mms. Patients can typically pass the smaller stones in 
the urine. However, larger stones (e.g. > 10mm) may require lithotripsy and surgical or 
endoscopic removal. A kidney stone may not cause symptoms until it moves around within the 
kidney, passes into the ureter, bladder, or urethra. 
Stone Events 
In this study, kidney stone events are defined as follows: 
•
A stone event is defined as the occurrence of one or more of the following symptoms
due to a kidney stone that may or may not require medical intervention:
o
Abdominal, flank or groin pain, sometimes associated with nausea and vomiting.
o
Macroscopic hematuria (visible blood in the urine).
o
Urinary tract infection (cloudy or foul-smelling urine, more frequent and/or painful
urination than normal, persistent need to urinate and/or urinating small amounts).
•
Stone events may also be defined by subject-reported stone passage or by medical
procedures to remove identified kidney stones (e.g. lithotripsy, endoscopy, surgery).
•
An increase in number of kidney stones as seen in a kidney ultrasound would also be
defined as a stone event.
Duration between stone events: if symptoms of a stone event occur simultaneously or close in 
time to another kidney stone event symptom, the investigator can decide whether or not this 
should be reported as the same stone event or as a new, separate stone event. 
Assessments of stone events will be collected by ultrasound (renal imaging) (see Section 
10.6.2 below) as well as subject-reported stone events or symptoms of events (see definition 
above). Historical kidney stone events and related symptoms for the past three years 
preceding study entry will be asked at screening. During the baseline and treatment period, 
information will be collected concerning occurrence of self-reported kidney stone events 
and related symptoms. This information will be captured by completing the Adverse 
Event eCRF at each visit throughout the study. 
Frequency of kidney stone events will be evaluated after 52 weeks of treatment. 
10.4  Speckle Tracking and Traditional Echocardiography 
Speckle Tracking Echocardiography (STE) is currently evaluated as a method to detect and 
quantify effects of oxalate deposits in the heart muscle (Lagies et al., 2013, 2019). STE is 
considered to be a feasible tool for discovering subtle changes of myocardial performance and 
identifying PH patients at risk for serious cardiac damage.  

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Speckle Tracking and traditional echocardiography will be performed twice during 
screening/baseline and at week 24 and 48 (+/- 2 weeks) during the treatment period. The 
examination will be performed locally using specific equipment as detailed in the site manual. 
Images will be interpreted centrally in a blinded manner. If the images are not meeting the 
quality criteria, the examination will be repeated within 4 weeks of the initial examination. For 
the week 48 examination, a repeat examination, if needed, should be done before end of 
treatment in week 52.  
Complete instructions for the collection, processing, storage and transfer of images will be 
provided in the imaging manual.  
STE results will be evaluated for changes in global longitudinal strain, including segmental 
changes, short-axis myocardial function, rotational displacement and apical sparing patterns. 
Traditional echocardiographic parameters will also be evaluated (e.g. Ejection Fraction, End 
Diastolic Volume, Medial to Lateral Diastolic Peak Velocity (e/é), Early to Late Ventricular 
Filling Velocity (e/a), Left Ventricular End Diastolic Dimension, Fractional shortening, 
Tricuspid Regurgitation by Doppler as an indicator of right ventricular/pulmonary pressure.). 
A positive treatment effect would be an improved myocardial function based on the above-
mentioned parameters, decreased global longitudinal strain, improved rotational displacement 
and reduced/removed apical sparing pattern. The treatment effect on STE parameters will be 
compared to traditional echocardiography parameters of left and right ventricular function to 
determine which assessment of cardiac function is more sensitive in these subjects. 
10.5  Quality of Life Questionnaire 
A questionnaire will be used to evaluate the Quality of Life for the participating subjects. The 
SF36v2 questionnaire will be used for the adult subjects and the CHQ/CHQ/PF50 for subjects 
5-18 years and their parents. The questionnaire will be completed by the subjects/parents 
during screening/baseline and during the clinical visits at weeks 8, 24, 40 and 52. 
10.6  Other Parameters for Evaluation of Treatment Effect 
The additional parameters described below will also be analysed for treatment effect.  
10.6.1 Quantification of O. formigenes 
The possibility to monitor the natural occurrence of O. formigenes bacteria and the presence of 
the O. formigenes drug before, during and after treatment with OC5 is an important tool for 
control of the pharmacodynamics of the drug. To date, two different genotypes of naturally 
occurring Oxalobacter formigenes have been identified, genotype 1 and 2 (groups I and II). 
Oxabact, or OC5, is of the strain HC-1 of the Oxalobacter formigenes genotype 1.  A real-time 
quantitative PCR assay will be used that permits determination of the numbers of both O. 
formigenes genotype 1 and genotype 2 in faecal samples.  
Faecal samples will be collected at subject’s home and shipped to central laboratory MVZ 
Institut für Mikroökologie GmbH, Herborn, Germany. 
A positive treatment effect on the result from analysis of number of O. formigenes should show 
an increased number of O. formigenes genotype 1 during treatment period. Earlier studies have 
shown that O. formigenes genotype 2 have increased in the OC5 treated group, but not in the 
placebo group indicating a transfer of oxalate from plasma to the intestine mediated by OC5 
treatment. O. formigenes genotype 2 will also be monitored for this reason. 

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The association between change in O. formigenes and change in total plasma oxalate will also 
be evaluated.  
 
10.6.2 Ultrasound 
Ultrasound of the kidneys will be done at the site hospital. Images will be sent for central 
reading in a blinded manner. The examination will be standard and described in detail in the 
imaging manual.   
Ultrasound images will be evaluated to determine the grade of nephrocalcinosis and the amount 
of kidney stones.  
For nephrocalcinosis, the grading system using the ultrasound will be using 0-3 grades (Boyce 
et al., 2013) 
• grade 0: no echogenicity 
• grade 1: mild echogenicity around medullary pyramid borders 
• grade 2: moderate echogenicity around and inside pyramids 
• grade 3: severe echogenicity of entire pyramids 
10.6.3 Twenty-Four-Hour Urine Samples 
Twenty-four-hour urine samples for analysis of urinary oxalate, urinary calcium, urinary 
glycolate, urinary magnesium, urine citrate, urine urea, urine creatinine, urine phosphorus 
excretion, pH, osmolality and urine volume will be taken at subject´s home and sent to central 
laboratory TDL, London, UK. Urine calcium oxalate crystals and pH will also be analysed 
from this sample. Urinary oxalate will be analysed with a colorimetric enzymatic assay using 
oxalate oxidase, which oxidizes oxalate to carbon dioxide and hydrogen peroxide. The analyses 
will be described in more detail in the lab manual. 
10.6.4 Plasma Sample – Other Endpoints 
Plasma samples will also be analysed for magnesium, phosphorus, citrate, calcium, glycolate, 
BUN, ALP, bicarbonate, CRP, WBC, creatinine and cystatine C for evaluation of other 
endpoints. The details of sampling and analysis of these parameters will be outlined in the lab 
manual.  
 
 

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11 ASSESSMENT OF SAFETY 
The safety parameters to be assessed are: 
• Adverse Events 
• Laboratory safety measurements  
• Vital signs 
• Physical examination 
11.1 Definition of Adverse Events 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. AEs 
therefore include e.g. worsening of a pre-existing illness and any injury or accident. This refers 
also to symptoms due to a pre-existing allergy, e.g. if seasonal allergy symptoms are within 
what is normally experienced, they should not be recorded as adverse events. If the symptoms 
are worse than what is normally experienced, then they should be recorded as adverse events.  
An AE does not include: 
• Symptoms of the underlying disease (with exception of kidney stone events) that might be 
reasonably anticipated to come and go, or progress, given the nature and severity of the 
condition. However, if the progression of the disease escalates, resulting in hospitalization, is 
life-threatening, or is fatal, then progression of the disease should be reported as an AE of 
serious nature; 
• Expected variations in severity of disease signs and symptoms that have previously been 
reported in the subject’s medical history; 
• Pre-planned medical or surgical procedures (e.g., surgery, tooth extraction, or transfusion) 
[Note: The condition that leads to the procedure may be an AE]; 
• Overdose of study drug without any clinical signs or symptoms; or 
• Clinically significant laboratory values. If abnormal laboratory values are accompanied by 
abnormal signs or symptoms, the signs or symptoms are considered an AE and should be 
recorded as such. Abnormal laboratory values associated with the underlying disease are not 
an AE unless the values unexpectedly worsen. Abnormal laboratory values will be recorded in 
the study database. 
Adverse Drug Reaction (ADR) 
An AE is defined as an adverse drug reaction (ADR) if further analyses prove that the AE is 
caused or partially caused by the investigational product. This includes interaction, overdosing, 
abuse and development of addiction. Expected ADRs are also possible events due to the 
substance class of the investigational drug, expected from analogue conclusions or theoretical 
considerations related to toxicological, pharmacological or kinetic characteristics. 
 

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Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is one that suggests a significant hazard, contraindication, side 
effect or precaution that results in: 
• the subject’s death 
• is life-threatening* 
• requires inpatient hospitalization or prolongation of existing hospitalization ** 
• persistent or significant disability/incapacity; or 
• congenital anomaly/birth defect 
• corresponds to another important medical event as determined by the Investigator. 
*   Life threatening means that the subject was at immediate risk of death from the AE as 
it occurred, or it is suspected that the use or continued use of the investigational product 
would result in the subject‘s death. Life threatening does not mean that had an AE occurred 
in a more severe form it might have caused death. 
** Hospitalization requires over-night stay at the hospital. Outpatient treatment in an 
emergency room is not itself a SAE. Hospital admission and/or operations planned before 
or during a study are not considered SAEs if the illness or disease existed before the subject 
was enrolled in the study, provided that it did not deteriorate in an unexpected way during 
the study.  
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected unexpected serious 
adverse reaction.  
In cases of doubt on this issue, it is suggested that there should be a predisposition to report 
rather than not to report (see Section 11.3). 
11.2  Relationship to Study Drug 
The following relationships to study drug will be used in the study (in accordance with the 
WHO-UMC Causality Categories, Table 7).  Events classified as certain, probable/likely or 
possible will be considered related to study drug. 
Table 7: WHO-UMC Causality Categories 
Causality Term 
Assessment Criteria 
Certain 
• Event or laboratory test abnormality, with plausible 
time relationship to drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible 
(pharmacologically, pathologically) 
• Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
• Rechallenge satisfactory, if necessary 

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Probable/ 
Likely 
• Event or laboratory test abnormality, with reasonable 
time relationship to drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
Possible 
• Event or laboratory test abnormality, with reasonable 
time relationship to drug intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible) 
• Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
• Event or laboratory test abnormality 
• More data for proper assessment needed, or 
• Additional data under examination 
Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction 
• Cannot be judged because information is insufficient or 
contradictory 
• Data cannot be supplemented or verified 
 
11.3  Recording Adverse Events 
Each subject will be questioned about AEs at each visit/ following initiation of treatment. The 
question asked will be "Since your last visit have you had any health problems?" The 
information can also be obtained from signs and symptoms detected during each examination, 
observed by the study personnel or spontaneous reports from the study subjects or by lab 
results. 
The investigator is to record in the eCRFs all directly observed AEs, all AEs as a response of 
the open question and all AEs spontaneously reported by the subject during the study.  
The investigator will record all AEs by: 
• Description of event (recorded in standard medical terminology and avoiding 
abbreviations), 
• Start and end date, 
• Intensity/grade*  
• Seriousness (serious or not serious, according to definition), 
• Causal relationship, (certain, probable/likely, possible, unlikely, conditional/unclassified, 
unassessable/unclassifiable)  
• Action taken, (none, treatment required, study drug interrupted, subject withdrawn, other) 
• Outcome of the AE (recovered, recovered with sequelae, death, not recovered) 
The Sponsor or delegate will code all AEs and SAEs using MedDRA. 

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* For each reported AE, the intensity (grade) will be recorded. The following grades of
intensity are to be used (CTCAE version 4.0):
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
A Semi-colon indicates ‘or’ within the description of the grade. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
If the intensity /grade changes within 24 hours the maximum intensity should be recorded.  If 
the intensity changes over a longer period of time, the changes should be recorded in the eCRF. 
11.4 Reporting Adverse Events 
Adverse Event reporting for each subject shall start at the initiation of study treatment, (i.e. 
from FDD). The reporting shall continue during the course of the study (i.e. until EOS). 
Thus, reported AEs include: 
•
all AEs that occur during the treatment phase
•
all AEs that occur during the safety follow-up period
Spontaneously reported events by study subjects in between planned visits shall also be 
reported. AEs should be reported for all subjects, independent of treatment assignment. 
NON-SERIOUS AEs are to be reported in the eCRF. 
SAEs are to be reported by the investigator within 24 hours of awareness. The eCRF and the 
initial SAE form (provided in the Investigational Site File) are both to be completed within this 
time, and the latter submitted to ProductLife Department via fax (please see SAE report form 
for fax number) or email (safety@productlife-group.com).  
In case of any question related to SAE reporting please contact Drug Safety Physician/ Medical 
Monitor, see contact information in Table 1. All SAEs must be reported whether or not 
considered drug related. The site is required to send the available SAE information even if the 
data is incomplete. 
After receipt of the initial report, ProducLife will forward the information to OxThera within 
24 hours. ProductLife Pharmacovigilance Department will work with OxThera to review the 
information received and contact the site to request any missing information/amendments 
needed. When follow-up information is obtained by the investigator it should also be forwarded 

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to the Medical Monitor within 24 hours. The report should be marked “Follow-up report”. Any 
follow-up received should be treated in the same way as initial reports. 
The investigator will submit copies of SAE reports to the independent ethics committee 
concerned as required by local regulations. All serious and unexpected adverse events will be 
reported to the European authorities as per regulations.   
Adverse Drug Reactions, which are unresolved at the end of the safety follow-up period should 
be followed by the Investigator until the event has resolved or, if persistent, has been assessed 
as “chronic” or “stable”.  This data is not recorded in the eCRF.  
An Unexpected Adverse Reaction is any adverse reaction, of which the specificity or severity 
is not specified in the current Investigator’s Brochure for the study drug. 
A SUSAR is a Suspected Unexpected Serious Adverse Reaction.  All SUSARs that are 
possibly, probably or definitely related to OC5 are subject to expedited reporting to Regulatory 
Authorities, Ethic Committees and participating investigators in accordance with local 
requirements in force and the ICH guidelines for Good Clinical Practice (GCP) and the EU 
Directive 2001/20/EC. ProductLife Pharmacovigilance Department will be responsible for 
ensuring expedited reporting of SUSARs. 
11.4.1 Emergency Unblinding 
The investigator is responsible for ensuring that there are procedures and expertise available to 
handle emergencies during the study. In the event the investigator considers it necessary to 
know the identity of the study substance to manage a specific serious adverse event, the 
treatment may be un-blinded for that particular subject. The responsibility to break the 
treatment code in emergency situations resides solely with the investigator and the investigator 
has unrestricted and immediate access to emergency envelopes available at the site to break the 
treatment code. The investigator shall immediately inform the Medical Monitor if the treatment 
code is broken. 
11.5  Anticipated Adverse Events 
11.5.1 Review of Available Data  
OC3 has been evaluated in several clinical studies in patients with PH; one 28-day phase I/II 
study (OC3a), one 24-week double blind placebo-controlled multicentre international phase 
II/III clinical study including a 24-week open-label extension study (OC3b), and one 24-week 
double-blind placebo-controlled multicentre international phase II/III clinical study (OC3b 
buffer formulation). OC5 has been evaluated in one double-blind placebo-controlled 
multicentre international phase II study and one ongoing phase II open-label study, see Table 3. 
In summary OC3 and OC5 have been evaluated in over 100 subjects receiving a dose of up to 
109 CFU twice a day. The continuous exposure to study drug ranged from 4 weeks up to 3 
years. Both OC3 and OC5 were considered safe and well tolerated in all clinical studies. 
Review of the safety data from the complete studies indicate that subjects may experience 
headache and gastrointestinal symptoms including abdominal pain, constipation, nausea, 
vomiting, diarrhoea, and flatulence.  
No treatment related Serious Adverse Events for Oxabact were reported in patients with PH.  
In all studies, the majority of adverse events were reported as mild and unlikely related to the 
treatment. In the placebo-controlled studies, the adverse events were equally distributed 
between OC3/OC5 and placebo. 
 

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11.5.2 Safety Data for OC5-DB-01 Study 
Twenty-eight subjects were randomized in the OC5-DB-01 trial, and half of them were treated 
with active drug. The first subject was enrolled in December 2013 and the last patient last visit 
(LPLV) was in January 2015. No serious related adverse events were reported in the trial.  
The AEs are summarized in Table 8 and Table 9. In general, the treatment groups appeared to 
be comparable, although some slight differences could be noted. No SAE was reported in the 
placebo treatment group, whereas three subjects in the OC5 treatment group reported a SAE. 
Slightly higher number of subjects reported Renal and urinary disorders in the OC5 treatment 
group (n=4) as compared to the placebo treatment group (n=0). Slightly higher number of 
subjects reported Nervous system disorders in the placebo treatment group (n=5, whereof all 
reported headache) as compared to the OC5 treatment group (n=1, reported both headache and 
dizziness). 
Table 8: Overview of Adverse Events for Study OC5-DB-01 
 
OC5 (N=14) 
Placebo (N=14) 
Total (N=28) 
 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Any adverse events 
10 (71.4%) 
41 
12 (85.7%) 
26 
22 (78.6%) 
67 
Any serious adverse events 
3 (21.4%) 
3 
0 
0 
3 (10.7%) 
3 
Adverse events by relationship 
NOT RELATED 
9 (64.3%) 
26 
10 (71.4%) 
15 
19 (67.9%) 
41 
POSSIBLE 
6 (42.9%) 
14 
6 (42.9%) 
10 
12 (42.9%) 
24 
PROBABLE 
0 
0 
0 
0 
0 
0 
DEFINITELY 
1 (7.1%) 
1 
1 (7.1%) 
1 
2 (7.1%) 
2 
Adverse events by intensity 
MILD 
9 (64.3%) 
28 
12 (85.7%) 
23 
21 (75.0%) 
51 
MODERATE 
6 (42.9%) 
11 
2 (14.3%) 
2 
8 (28.6%) 
13 
SEVERE 
2 (14.3%) 
2 
1 (7.1%) 
1 
3 (10.7%) 
3 
 
Adverse event leading to  
withdrawal 
0 
0 
0 
0 
0 
0 
 
Adverse event leading 
 to death 
0 
0 
0 
0 
0 
0 
n: Number of subjects; m: Number of mentions 
 

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Table 9: Summary of Types of Adverse Events Experienced in OC5-DB-01 (Safety Analysis Set) 
 
OC5 
(N=14) 
Placebo 
(N=14) 
Total 
(N=28) 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Any adverse event 
10 (71.4) 
41 
12 (85.7) 
26 
22 (78.6) 
67 
Gastrointestinal disorders 
6 (42.9) 
14 
5 (35.7) 
7 
11 (39.3) 
21 
Infections and infestations 
3 (21.4) 
3 
4 (28.6) 
5 
7 (25.0) 
8 
Nervous system disorders 
1 (7.1) 
2 
5 (35.7) 
5 
6 (21.4) 
7 
Respiratory, thoracic and mediastinal disorders 
2 (14.3) 
3 
3 (21.4) 
4 
5 (17.9) 
7 
Renal and urinary disorders 
4 (28.6) 
7 
0 
0 
4 (14.3) 
7 
Renal colic 
2 (14.3) 
3 
0 
0 
2 (7.1) 
3 
Renal pain 
2 (14.3) 
2 
0 
0 
2 (7.1) 
2 
Calculus urethral 
1 (7.1) 
1 
0 
0 
1 (3.6) 
1 
Pyelonephritis 
1 (7.1) 
1 
0 
0 
1 (3.6) 
1 
General disorders and administration site conditions 
3 (21.4) 
6 
1 (7.1) 
1 
4 (14.3) 
7 
Skin and subcutaneous tissue disorders 
3 (21.4) 
3 
0 
0 
3 (10.7) 
3 
Musculoskeletal and connective tissue disorders 
1 (7.1) 
1 
1 (7.1) 
1 
2 (7.1) 
2 
Injury, poisoning and procedural complications 
1 (7.1) 
1 
0 
0 
1 (3.6) 
1 
Psychiatric disorders 
1 (7.1) 
1 
0 
0 
1 (3.6) 
1 
Ear and labyrinth disorders 
0 
0 
1 (7.1) 
1 
1 (3.6) 
1 
Investigations 
0 
0 
1 (7.1) 
1 
1 (3.6) 
1 
Reproductive system and breast disorders 
0 
0 
1 (7.1) 
1 
1 (3.6) 
1 
n: Number of subjects; m: Number of mentions 
Adverse events are coded according to MedDRA version 16.1 
Percentage is based on number of subjects in safety analysis set 
Ten subjects (71%) in the OC5 group experienced an AE, which was similar to the number in 
the Placebo group (12; 86%). A greater number of individual AEs were mentioned in the OC5 
group than in the Placebo group (41 versus 26). Four subjects in the OC5 group experienced 
renal and urinary disorders (seven mentions in total); no AEs in this system organ class were 
reported in the Placebo group. 
The occurrence of AEs was similar in the two groups. Although more renal and urinary 
disorders were experienced by subjects in the OC5 group than in the Placebo group (four 
subjects [29%] versus no subjects [0%]), only one occurrence was considered related to the 
treatment (Subject SCR01-0002; kidney pains, moderate, possibly related). The subjects in the 
OC5 group had a more pronounced reduction in renal function than the placebo subjects at 
baseline. Mean baseline eGFR was lower in the OC5 group than in the placebo group 
(97.5±38.7 versus 123.1±45.4 mL/min/1.73 m2), and renal and urinary disorders were more 
common in the OC5 group (11 cases versus eight cases). Most notably, four subjects in the 
OC5 group had a history of chronic renal failure, whereas no subjects in the placebo group had 
been affected by this condition.   
Two AEs were judged to be definitely related to treatment. Subject SCR01-0001 (OC5) 
experienced a case of mild rumbling stomach, which began the day that treatment commenced 
and resolved the day after treatment ended. Subject SCR07-0004 (Placebo) experienced a case 
of mild diarrhoea the day after treatment started. 
Four AEs were of at least moderate severity and judged to be possibly related to the treatment: 
a moderate case of gastroenteritis (OC5; SCR01-0018), the aforementioned case of kidney 
pains (OC5; SCR01-0002), a moderate case of increased bowel movements (OC5; 
SCR03-0005) and a case of severe headaches (Placebo; SCR07-0004). No AEs required 
changes of dose. 
 

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11.5.3 Safety Data for the OC5-OL-01 Study 
The OC5-OL-01 study started in May 2014 and ended in January 2020. Fourteen subjects were 
screened and 12 subjects were enrolled in the study and received study drug. This study 
included late-stage patients with ESRD who were on dialysis. Most of these subjects were on 
a waiting list for transplantation. Eight subjects continued into the continued treatment phase 
of the study. There were no severe nor serious related adverse events for Oxabact in this study.  
Overall the safety data accrued to date would suggest that the OC5 drug product is safe and 
well tolerated and appears to have a similar safety profile as the earlier OC3 drug product. 
Further safety information of the OC5-OL-01, OC5-DB-02 and OC5-OL-02 studies has been 
detailed in the current version of the Oxabact Investigator’s Brochure. 
11.5.4 Systemic Infections due to O. formigenes  
O. formigenes is a commensal bacterium in the intestinal tract and is a strict anaerobe. 
Following an extensive search of the literature, there have been no reports of local or systemic 
infections where O. formigenes have been isolated.  Preparations of O. formigenes have been 
administered to rats, pigs and humans without any apparent toxicity or side effects including 
local or systemic infections. O. formigenes is dependent on oxalate as carbon source and cannot 
use any other carbohydrate source. In the completed clinical studies, no subject experienced 
any infection due to O. formigenes.  
Any subject who develops signs and symptoms of bacteremia requiring hospitalization should 
be evaluated to identify the source of infection (e.g. lung, GI tract, meningeal). Evaluation for 
the source of bacterial infection should include clinical and laboratory tests and cultures for 
common pathogens. Empiric antibiotic treatment should include coverage for common 
pathogens. It is recommended that an Infectious Diseases Specialist be consulted to assist in 
the assessment and management of the subject. 
O. formigenes has shown sensitivity to chloramphenicol, doxycycline, erythromycin, and 
tetracycline. In the event of unexpected infection caused by the study medication erythromycin 
is the recommended first line antibiotic therapy in children and adults, and tetracycline is the 
recommended second line antibiotic therapy in older children and adults. If common pathogens 
have been excluded or if the infection is not responding to erythromycin or tetracycline the 
study medication should be stopped until further evaluation. 
11.5.5 Elevated Levels of Plasma Formate 
Since Oxalobacter formigenes converts oxalate to formate in the intestine, there may 
theoretically be a possibility of elevated plasma formate levels following administration of high 
doses of OC5. However, formate is metabolized by a number of bacteria in the gut microbiota. 
Formate is a metabolite of methanol responsible for the toxicity observed with methanol 
poisoning. Typically, toxic effects require prolonged exposure to elevated plasma formate 
levels. 
The potential for elevated plasma formate levels following administration of OC5 is 
theoretically limited due to the limited availability of endogenous oxalate. Over 100 subjects 
have been exposed to date to Oxabact (OC3 and OC5) with doses up to NLT 109 CFU in studies 
up to 12 months. There have been no signs or symptoms of elevated formate plasma levels, 
metabolic acidosis or methanol poisoning. The main manifestations of methanol poisoning are 
metabolic acidosis and ocular toxicity. Any subject who develops signs and symptoms of 
metabolic acidosis should be evaluated to identify the source (e.g. evaluation of serum 
bicarbonate, blood pH, anion gap, osmolality gap and plasma formate).  

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Formate accumulation in plasma is the main reason for acidosis in early, uncomplicated stages 
of metabolic acidosis. Metabolic acidosis is characterized by low blood pH (arterial pH < 7.38 
or venous pH < 7.34) or low levels of serum bicarbonate, HCO3-(< 18 mmol/L). Decreased 
levels of serum bicarbonate will serve as an indication of elevated levels of formate. The OC5-
DB-02 study will investigate this early sign of elevated plasma formate as part of routine safety 
labs. Low levels of serum bicarbonate should trigger determination of the anion gap and the 
osmotic gap in order to confirm or rule out the diagnosis of metabolic acidosis due to elevated 
formate levels.  
If metabolic acidosis is diagnosed, the acidosis should be corrected as quickly as possible and 
therapy provided, if appropriate. If a diagnosis due to elevated formate levels cannot be 
excluded or if the metabolic acidosis cannot be corrected by standard of care the study 
medication should be stopped until further evaluation. Further evaluation should then include 
levels of plasma formate and visual disturbance test. 
11.6  Laboratory Safety Measurements 
The laboratory safety tests include:  
• Haematology: Erythrocytes, Leucocytes, Lymphocytes, Monocytes, 
Neutrophils, Basophils, Eosinophils, Platelets, Haemoglobin, Haematocrit, 
MCV, MCHC.  
• Chemistry:  Blood Urea Nitrogen (BUN), electrolytes (Na+, K+, Mg++, 
Ca++, HCO3-, Cl), glucose, albumin, alkaline phosphatase, ALT, AST, total 
bilirubin, and total protein.  
• FSH for postmenopausal women (see Section 7.3) at the screening visit only.  
• Pregnancy test for women of childbearing potential at baseline and week 52. 
• Random Urine (Urinalysis): protein, glucose, pH. 
Laboratory parameters for safety assessment from haematology and chemistry will be assessed 
at the central laboratory BARC. Urinalysis will be done at the local lab at each clinic. 
Laboratory safety tests will be performed as specified in Table 5.  
11.7  Vital Sign Measurements 
Vital sign measurements on study include temperature and blood pressure (systolic and 
diastolic), heart rate, respiratory rate (assessed after 5 minutes resting in a supine position) and 
weight. Weight will be measured using a calibrated scale with the subject lightly clothed and 
shoes off. Height will be measured using a calibrated wall mounted stadiometer. Height should 
be reported for all subjects in whom the Schwartz equation is used to determine eGFR. This 
would apply to children (subjects under 18 years of age) and to any subject who turn 18 during 
the study period. For subjects who are adults at study start, height will only be recorded at 
screening. 
11.8  Physical Examinations 
Physical examinations include appearance, gastrointestinal system, dermatological system, 
EENT, head and neck, cardiovascular system, respiratory system, musculo-skeletal system, 
peripheral nervous system. Additional examinations may be done at the Investigators 
discretion. 

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11.9  Pregnancy 
If a subject becomes pregnant during the course of the study the subject must immediately 
contact the Principal Investigator who should complete the pregnancy form and report the 
pregnancy within 24 h and send the form to ProductLife Limited. The administration of study 
medication should immediately be stopped, i.e. the subject will be withdrawn from study 
treatment. The subject must be followed until birth and the birth outcome must be documented 
within 6 to 8 weeks on the pregnancy form (detailed instruction can be found in the Safety 
Management Plan). 
11.10 Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) is the primary data and safety advisory group 
for the Sponsor (OxThera) consisting of independent clinical and statistical experts for study 
OC5-DB-02. Treatment with Oxabact has been shown to be well tolerated with no particular 
safety concerns in six completed studies, and one ongoing interventional study.  
The DSMB will periodically review safety data, evaluate excess adverse effects and judge 
whether the overall integrity and conduct of the trial remain acceptable, and make 
recommendations to the Sponsor. The DSMB will meet shortly after study start, and then have 
regular meetings every 3-4 months. During the meetings, the DSMB will review general safety 
data (reported AEs, SAEs, SUSARs, safety labs and other safety variables that may be 
applicable) and will not be unblinded to treatment assignment, unless specifically requested by 
the DSMB. The DSMB will discuss their findings in closed sessions and convey their 
recommendations to the Sponsor in an open session in which the sponsor attends to make 
necessary decisions from a safety perspective. 
The DSMB will be authorized to make recommendations to the Sponsor regarding safety 
issues, study conduct, and modifications to or termination of the study in the event that 
significant safety concerns arise during the study conduct. There will be no pre-defined 
discontinuation rules or formal statistical analyses performed as part of the DSMB to assess 
termination of the trial for efficacy or futility.  
The DSMB will be advisory to the clinical trial leadership group at the Sponsor. The Sponsor 
will be responsible for promptly reviewing the DSMB recommendations, formulating 
decisions whether to continue or terminate the trial, and determine whether amendments to the 
protocol or changes in study conduct are required from a safety perspective. 
 
 

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12 STATISTICAL METHODS 
12.1  Study Populations 
The efficacy population (Full Analysis Set, FAS) will include all randomized subjects who had 
at least baseline, one post-baseline assessment and received at least one dose of study 
medication.  
The evaluable population (Per Protocol Analysis Set) will include all randomized subjects 
included in the FAS who have taken at least 80% of scheduled doses of study medication, as 
judged by dispensation and return of study drug, and who provide at least two eligible 
measurements of plasma oxalate during treatment. Protocol deviations will be evaluated, and 
any further exclusions from PP will be decided prior to database lock and unblinding. 
The primary and secondary efficacy analyses will be based on the efficacy population as well 
as the evaluable population respectively and as randomized. The efficacy population will be 
the primary population for efficacy analyses. 
The safety population will consist of all randomized subjects who receive at least one dose of 
study drug. Safety analyses will be based on the safety population and as treated.   
12.2 Tests of Hypotheses and Significance Levels  
The mixed effect repeated measures model will be utilized to compare the treatment arms with 
respect to the primary endpoint with the null hypothesis that there is no effect of treatment 
(active treatment versus placebo) and the alternative hypothesis that there is an effect of 
treatment (active treatment versus placebo).  
H0: There is no effect of treatment (active versus placebo) on the 52-week change 
from baseline for total plasma oxalate. 
 
HA: There is an effect of of treatment (active versus placebo) on the 52-week change 
from baseline for total plasma oxalate. 
Statistical analyses will be performed using a two-sided significance level of 0.05.  
A fixed sequence stepwise multiple testing procedure at the 0.05 level will be performed in the 
pre-specified order of 1) plasma oxalate, 2) eGFR and 3) kidney stone events. When the 
hypothesis tested for an endpoint is statistically significant at the 0.05 level then the subsequent 
test will be performed at the 0.05 level. When a hypothesis test is not rejected at the 0.05 level 
then the subsequent analyses will only be considered descriptive. 
12.3  Sample Size Calculation 
In a previous OxThera study OC3-DB-02, with a total of 11 subjects (7 on active treatment, 4 
on placebo) having a baseline eGFR <90 ml/min/1.73 m2, a mean difference from baseline 
(screening) in total plasma oxalate concentration of - 4.964 (SD=5.219) μmol/L between active 
treatment versus placebo was observed after 24 weeks of treatment. Furthermore, OxThera 
study OC5-DB-01 showed a mean difference in total plasma oxalate of -5.299 (SD=3.235) 
after 8 weeks of treatment in a total of 9 subjects (7 active, 2 placebo) in subjects with baseline 
eGFR <90 ml/min/1.73 m2. 
Since for study OC5-DB-02 multiple plasma oxalate measurements will be taken at visits 1, 2, 
3, 4, 5, 6, 7, 8, 9 and 10, the most appropriate statistical model for the primary endpoint is a 
mixed-effect repeated measures model. It is expected that at week 52 the difference may be 

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larger than what has been observed in the previous study OC5-DB-01 at 8 weeks. Therefore, 
for the calculation a conservative mean difference of -5.50 with SD of 4.00 is assumed. Using 
the MRMM model in a two-sided approach with α=5%, β=10% (and thus power=90%), a 1:1 
allocation ratio and assuming a within subject correlation of 0.70, the sample size is assessed 
at 9 subjects for each group. With this sample size, a difference of -6.00 with an SD of 4.50 
may be considered to be statistically significant (Oxabact vs. Placebo). Considering 18 
completers are needed based on this calculation, an estimate of 22 subjects will be randomized 
to account for possible drop-outs. 
To account for the possiblity of higher than observed variability, please find below Table 10 
sample size estimates for various configurations. 
Table 10: Sample Size Calculation Primary Endpoint 
 Difference in plasma oxalate between Oxabact and Placebo 
SD 
-4.50
-5.00
-5.50
-6.00
-6.50
-7.00
3.00 
7:7 
6:6 
5:5 
4:4 
4:4 
3:3 
3.50 
10:10 
8:8 
7:7 
6:6 
5:5 
4:4 
4.00 
13:13 
10:10 
9:9 
7:7 
6:6 
6:6 
4.50 
16:16 
13:13 
11:11 
9:9 
8:8 
7:7 
5.00 
20:20 
16:16 
13:13 
11:11 
10:10 
8:8 
5.50 
24:24 
19:19 
16:16 
14:14 
12:12 
10:10 
Considering the anticipated 18 completers using a MRMM model in a two-sided approach with 
α=5%, and a within subject correlation of 0.70, the sample size evaluated at 9 subjects for each 
group yield approximately 90% power to identify a difference (SD) of 4 (3) ml/min/1.73m2 in 
eGFR change from baseline at week 52 between the treatment arms (Table 11). 
Table 11: Power Calculations for Change from Baseline in eGFR 
 Difference in eGFR between Oxabact and Placebo 
SD 
1 
2 
3 
4 
5 
6 
3.00 
0,12786 
0,37707 
0,69504 
0,90883 
0,98450 
0,99856 
4.00 
0,08973 
0,23426 
0,45726 
0,69504 
0,87028 
0,95953 
5.00 
0,07133 
0,16555 
0,31637 
0,50645 
0,69504 
0,84237 
6.00 
0,06078 
0,12786 
0,23426 
0,37707 
0,53923 
0,69504 
7.00 
0,05402 
0,10488 
0,18371 
0,29169 
0,42248 
0,56250 
8.00 
0,04935 
0,08973 
0,15065 
0,23426 
0,33866 
0,45726 
Due to the limited number of patients in this rare disease population, and the limited amount 
of historical data, it is not possible to define the expected magnitude of change during the study 
period. Analysis of available data from the OC3-DB-02 study gives an indication of the change 
in the full population over six months treatment as indicated above, although the older less 
potent OC3 study drug was used in this study. Furthermore, the PH population is very 
heterogeneous, and subjects will likely show an individual response to treatment.  

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12.4 Primary Endpoint 
Change from baseline in total plasma oxalate concentration will be calculated at each visit as 
the visit value minus the mean of the three measurements during baseline. The primary 
statistical analysis will be performed using MRMM analysis based on the FAS with a model 
that includes the following fixed effects: treatment group, baseline plasma oxalate value, 
randomization stratum (PH type 2, PH type 3, not PH type 2 or 3 and baseline urinary oxalate 
excretion ≤ 1.87 mmol/24h/1.73 m2, not PH type 2 or 3 and baseline urinary oxalate excretion 
> 1.87 mmol/24h/1.73 m2), week, and week-by-treatment interaction. The primary comparison
will be between the Week 52 changes from baseline in OC5 and placebo. An autoregressive of
order 1 (AR (1)) variance covariance matrix will be used for the within subject variation in the
MRMM model. In case there is a convergence problem the following variance covariance
matrix structures will be used in the order of 1) unstructured, 2) Toeplitz, and 3) compound
symmetry (CS). The first (co)variance structure which does not have convergence problem will
be the one used for the analysis. Comparisons at other weeks will also be performed
respectively.
Values and change from baseline over time will be summarized. Mean total plasma values over 
time for both treatment groups will be plotted in addition to a plot with the data over time 
presenting one line for each subject. Total plasma oxalate observed minimum and maximum 
post baseline values and change from baseline will also be summarized and plotted. 
Additionally, and for each subject a plot presenting both total plasma oxalate and eGFR over 
time will be produced to ilustrate how total plasma oxalate and eGFR change together. 
A sensitivity analysis will also be performed using MI prior to applying the MRMM analysis. 
As both maximum likelihood (used in the MRMM) and MI assume at least MAR missing data 
will be evaluated and described (Ratitch et al., 2013). To assess the robustness of the primary 
analysis to possible deviations from the MAR assumption a PMM will be used to support the 
evaluation of data with missingness mechanism not at random, MNAR. 
Additionally, a second analytical method approach will be provided as supportive analyses (i.e. 
ANCOVA and/or AUC) and will be further defined in the SAP. 
Secondarily the same analysis will be produced based on the PP analysis set. 
12.5  Key Secondary Endpoints 
•
Change from baseline in kidney function (i.e. eGFR slope) after 52 weeks of treatment 
will be analysed in the same way as the primary endpoint. Estimated GFR will be 
calculated for the primary analysis based on the 2009 creatinine-based “Schwartz 
bedside” equation (for children below 18 years of age) and the 2009 creatinine-based 
CKD-EPI equation for adults. For subjects between 18 and 23 years (both inclusive) of 
age at screening visit 1, eGFR will be calculated as the average of the eGFR values 
based on the pediatric and adult equations (Ng et al., 2018). The mean value of the three 
values obtained at visit 1, 2 and 3 will be considered as the baseline eGFR value for the 
statistical evaluation. Subjects will continuously be evaluated using the same eGFR 
equation as when entering visit 1. Difference in slopes using the proposed time-by-
treatment interaction will be presented as well. LS means will be determined for each 
visit. Supportive summaries will use alternative eGFR equations based on the Cystatin-
C based CKiD/CKD-EPI 2012 equations without modification for subjects between 18 
and 23 years. Historical renal function will be assessed in the context of on-study renal 

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function to determine the degree of progression of renal function decline (i.e. the slope) 
before and during the study.   
• Frequency of kidney stone events defined as  
o Subject- or investigator reported symptoms, or  
o Stone passages or removals, or 
o Increase in number of stones assessed by ultrasound 
after 52 weeks of treatment. 
Kidney stone events after 52 weeks of treatment will be summarized using descriptive 
statistics. Incidence rates and 95% CIs of kidney stone events (defined as the number of events 
divided by the total person-years) will be calculated along with the number of stone events and 
the number of subjects with a stone event. Treatment groups will be compared. 
12.6 Other Endpoints 
• Percent change from baseline in total plasma oxalate concentration after 52 weeks of 
treatment will be analyzed in the same way as the primary endpoint. 
• Subjects achieving ‘near-normalization’ of total plasma oxalate concentration (<10 
µmol/L) at least twice during weeks 24 to 52 of treatment will be summarized. The 
treatment arms will be compared using the stratified generalized Cochran-Mantel-
Haenszel test of general association including the appropriate stratification factors. 
Exact 95% CIs will be calculated for each treatment arm, and the common odds ratio 
across strata for the treatment arms. Wilson’s score method with continuity correction 
will be used to calculate a 95% CI for the difference in rates. 
• Change from baseline in myocardial function as measured by Speckle Tracking and 
traditional echocardiography will be summarized descriptively over time.  
• Change from baseline in free plasma oxalate after 52 weeks of treatment will be 
analysed in the same way as the primary endpoint. 
• Change from baseline in urinary oxalate excretion after 52 weeks of treatment.  
• Change from baseline in grade of nephocalcinosis as assessed by Ultrasound  
• 
Change in number of O. formigenes stool will be based on number of O. formigenes at 
week 52 compared to baseline in the active group versus placebo. The measurement at 
week 24 will be used as supportive data. Remaining time-points during the study will 
be used descriptively.  Both O. formigenes genotype 1 and genotype 2 will be analysed.  
• 
Association between change in O. formigenes in stool and change in total plasma 
oxalate concentration will be evaluated in the same way. The measurement at week 24 
will be used as supportive data. The method of analysis will be the same as for the 
primary and secondary endpoints. Remaining time-points during the study will be 
presented descriptively. 
• 
Change from baseline in score of Quality of Life scores as measured by SF36V2 or 
CHQ/PF50 questionnaires, depending on age, will be summarized over time and 
compared descriptively between the two treatment groups.   
• Change from baseline in markers for renal function, renal tubular capacity and 
inflammation in urine and plasma will be analysed as the difference between absolute 
change from baseline in the active group and absolute change from baseline in the 

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placebo group. The analysis will be based on the week 52 value compared to the mean 
of the three values from baseline for plasma-based analysis and the two values from the 
baseline 24 h urine collections for the urinary based analysis. The measurement at week 
24 will be used as supportive data. The method of analysis will be the same as for the 
primary and secondary endpoints. Remaining time-points during the study will be 
presented descriptively.   
12.7  Subgroup Analysis 
Aspects on Subgroup Analysis Based on Previous Studies 
A sub-group analysis has been made based on pooled historical data from treatment with OC3 
(OC3-DB-02) and OC5 (OC5-DB-01) where the combined patient population was divided into 
sub-groups based on kidney function, plasma oxalate concentration and urinary oxalate 
excretion at baseline. The purpose of the sub-group analysis was to see whether there were any 
detectable differences with regard to treatment response between the groups.   
Although the number of subjects in each group is small, the analysis showed that:  
o subjects with high Urinary oxalate excretion (above 1.87 mmol/24h per 1.73 
m2) 
o subjects older than18 years 
o subjects with eGFR <60 ml/min/1.73 m2 
tend to show a more pronounced treatment response measured as change in plasma oxalate 
concentration and/or change in eGFR over time.  The primary and secondary endpoints will 
therefore be analysed also in these sub-groups of subjects. 
 
Subgroup Analysis 
Subgroup analyses of the following endpoints will be performed, total and free oxalate 
concentration, eGFR, urine oxalate, stone events, O. formigenes in stool, Speckle-Tracking 
and traditional echocardiography. The analyses will be based on the following subgroups 
provided there is sufficient sample size: 
• Subjects with a baseline urinary oxalate excretion above and equal to or below 
1.87 mmol/L/24h/1.73 m2 respectively (mean of the two values during 
screening/baseline). 
• Subjects above or equal to and below 18 years of age at baseline.       
• Subjects with a baseline eGFR above or equal to and below 60 ml/min/1.73m2 
respectively (mean of the obtained values during screening/baseline calculated 
by the Schwartz CKiD (2009 creatinine-based “bedside Schwartz” equation for 
children (below 18 years of age) and 2009 creatinine-based CKD-EPI equation 
for adults).  
• Race.     
• Gender. 
• Progressors and non-progressors based on historic eGFR (i.e. eGFR prior to 
treatment start). 
• Use of vitamin B6 at baseline. 

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For the subgroup analyses, only the primary method of analysis will be used. Subgroups may 
also be analysed using alternative eGFR equations. No formal testing of subgroups will be 
performed due to small sample sizes. 
12.8 Safety 
The safety will be assessed through collection and analyses of adverse events (AEs), baseline 
medical conditions, laboratory tests, vital sign data and physical examinations. Listings of AE’s 
and SAE’s will be provided along with narratives. Adverse events will be categorized by SOC 
and Preferred Term from MedDRA. The focus of the adverse event summaries will be on 
treatment-emergent adverse events defined as occurring from the first dose in ePHex until;  
• up to 14 days after the last dose of double-blind treatment, or  
• the first day of open-label Oxabact treatment of ePHex-OLE,  
whichever occurs earlier. Treatment-emergent adverse events will be summarized using counts 
and percentages overall, serious, by severity, and by relationship to study product.  
Values over time and changes from baseline and shifts from baseline will be summarized by 
treatment group. Continuous parameters will be summarized by number of non-missing 
observations, mean, standard deviation, median, minimum, and maximum. Categorical 
parameters will be summarized by count and percent.  
12.9  Randomization 
This is a randomized, placebo-controlled double-blind multi-centre study. Subjects will be 
randomly assigned to OC5 or placebo in a 1:1 ratio. Subjects will be stratified firstly in an 
attempt to achieve an even distribution of PH type 2/type 3 patients and secondly to stratify the 
PH type 1 patients for a baseline urinary oxalate excretion above or below or equal to 1.87 
mmol/24h/1.73 m2 (based on the mean of the first two visits from screening/baseline).  
12.10 Demographics and Baseline Characteristics  
Demographic variables and other baseline characteristics will be summarized using descriptive 
statistics (mean, standard deviation, median, Q1, Q3, minimum and maximum) for continuous 
variables and counts and percentages for categorical variables. These summaries will be 
produced for the efficacy population, evaluable population and safety population. 
12.11 Statistical Analysis 
All statistical analyses will be further defined in a Statistical Analysis Plan (SAP). Any 
deviations from the SAP will be described and justified in the Clinical Study Report.  
12.11.1 Data Imputation 
Both maximun likelihood, as used in MRMM, and MI are the preferred methods to address 
missing data considered at least missing at randon. MRMM is the preferred method and uses 
all available data to provide unbiased estimates and therefore no imputation is required. 
Additional sensitivity analyses will be performed based on MI prior to the MRMM analyses 
and PMM. The extent and reasons for missing data will be evaluated. 
 
 

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13 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution should permit study-related monitoring, audits, IEC review and 
regulatory inspections, and should provide direct access to the source data/medical record. 
The monitor should verify that each subject has consented in writing to direct access to the 
original medical record/source data (by the use of written patient information and signed 
informed consent). During the monitoring, the data recorded in the eCRFs by the investigator 
will be checked for consistency with the source documents/medical record by the study monitor 
(source data verification). Any discrepancies of data should be documented and explained in 
the monitoring reports. 
For each subject, the medical records should include the minimum following information: 
• subject number and study id 
• date for information given, signing informed consent, screening 
• treatments given, including investigational product(s) 
• visits to the clinic 
• AE/SAE, if any 
• concomitant medication 
• time and reason for discontinuation, if any 
There are data that are recorded only on the eCRF, which are associated with protocol-specific 
procedures and not with normal clinical care practice. For such clinical data the investigator 
would not be expected to duplicate the information. Source data location will then be specified 
in the Investigator file. 
 

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14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1  Monitoring and Audits 
Monitoring of the study will be arranged by the sponsor according to GCP guidelines. 
Monitoring visits will be performed regularly to the study sites during the study, to ensure that 
all aspects of the protocol are followed. Source documents will be reviewed for verification of 
consistency with data recorded on the Case Report Forms and product accountability will be 
performed as a part of the monitoring visits.  
The study site may also be subject to quality assurance audits by the sponsor/CRO as well as 
inspection by the appropriate regulatory agencies. 
It is important that the investigator and their relevant personnel are available during the 
monitoring visits and possible audits/inspections, that study related records are made available, 
and that sufficient time is devoted to the monitoring process. 
14.2  Site Personnel 
Investigators and other key personnel shall provide curriculum vitae or equivalent, that will 
confirm their suitability for the clinical study. All investigators and key personnel should be 
listed together with their responsibilities in the study on a signature and delegation log. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study, including detailed knowledge of and training 
in all procedures to be followed. 
 
 

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15 ETHICS AND REGULATORY REQUIREMENTS 
15.1  Ethics Review 
It is the responsibility of the investigator to obtain written approval of the study protocol (incl. 
the patient information and informed consent) and subsequent protocol amendments from the 
IEC. The investigator should file all correspondence with the IEC, and a list of the IEC 
composition (names and position) should be filed in the Investigator File. A copy of the IEC 
approval should be forwarded to the sponsor.  
15.2  Ethical Conduct of the Study 
The study will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects adopted by the 18th World Medical Assembly, 
Helsinki, Finland, 1964 and later revisions and applicable ICH GCP guidelines. 
The investigator is responsible for complying with all reporting procedures applicable to their 
IEC. 
15.3  Written Informed Consent 
It is the responsibility of the investigator to give each subject, prior to inclusion in the study, 
full and adequate verbal and written information regarding the purpose and procedures of the 
study and the possible risks involved. The subjects must be informed about their right to 
withdraw from the study at any time, and that such withdrawal will not affect their future 
medical care, treatment or benefits to which the subject is otherwise entitled. The subjects 
should be informed that the results will be stored and analysed in a computer, maintaining 
confidentiality in accordance with local data protection laws. 
Furthermore, it is the responsibility of the investigator to obtain signed informed consent from 
all subjects prior to initiation of any study-related activity. As the study involves children, age 
specific patient information sheets and parent information sheets should be prepared, and 
subject and/or parental consenting should depend on the age of the subject. The investigator or 
his/her designated representative, who gave the verbal and written information about the study 
to the subject, must also sign the informed consent form. A copy of the written patient 
information must be handed to each subject, to bring home. The investigator will confirm the 
receipt of informed consent from each subject by a recording in the eCRF. The signed Informed 
Consent forms should be filed by the Investigator in the Investigator File for possible future 
audits and inspections.  
The investigator must always use the current IEC approved Patient Information/Informed 
Consent Form and it must not be changed without prior discussion with the sponsor and 
approval from the IEC. 
15.4  Regulatory Requirements 
The study will be performed in compliance with national regulatory requirements. As with the 
IEC, clinical trial authorization from the appropriate Regulatory Authority(ies) must be sought 
and obtained (as applicable to local country regulations), prior to the start of the study. The 
investigational product for this study will not be shipped to a study site until a copy of the 
applicable Regulatory Authority approval has been received by the sponsor. In addition, the 
Regulatory Authority(ies) must approve amendments (as instructed by OxThera), receive 

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SUSAR reports and annual safety updates or as required by local country regulations, and be 
notified of the end of the trial. 
 
 

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16 DATA HANDLING AND RECORDKEEPING 
16.1  Case Report Forms 
Study data for all subjects will be collected in a confidential fashion using an electronic Case 
Report Form (eCRF). All the information required by the protocol must be documented and 
any omissions explained. The investigator must review all eCRF entries for completeness and 
accuracy. Source documents, including all demographic and medical information, eCRFs and 
informed consent form for each subject in the study must be maintained by the Investigator. 
All information in the eCRFs must be traceable to the original source documents.  
The eCRF must be signed and dated by the investigator who takes responsibility for the 
accuracy, completeness and legibility of the data reported to the sponsor in the eCRFs. 
Medical history, concomitant medication and Adverse Events will be coded using standardized 
medical dictionaries (medical dictionary for regulatory activities; MedDRA).  
16.2  Retention of Records 
All essential documents must be safely retained by the investigator for at least 2 years following 
the date a marketing application is approved for the drug, for the indication for which it is being 
investigated; or if no application is filed or if the application is not approved for such indication 
for 15 years after the investigation is discontinued and the regulatory authorities are notified.   
16.3  Protection of Personal Data 
The completion of the Study involves the collection and processing of Personal Data. All 
processing of Personal Data at the clinic and by the sponsor must be carried out in accordance 
with national legislation concerning the protection of Personal Data. 
The investigator must ensure that the subject’s privacy is maintained. On the eCRF or other 
documents submitted to OxThera, subjects will be identified by a subject ID number only. 
Documents that are not submitted to OxThera (e.g., signed informed consent form) should be 
kept in a strictly confidential file by the investigator. 
The investigator shall permit direct access to subjects’ records and source document for the 
purposes of monitoring, auditing, or inspection by OxThera, authorized representatives of 
OxThera, Regulatory Authorities and IECs. 
As part of the required content of the informed consent, subjects will be informed that their 
records may be reviewed by OxThera’s designee and by regulatory agencies. Should access to 
medical record require a separate waiver or authorization, it is the Investigator’s responsibility 
to obtain such permission from the subject in writing before the subject is entered into the 
study. 

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17 FINANCING, INDEMNIFICATION AND INSURANCE  
The Clinical Trial Agreement (CTA) outlines the compensation and payment terms of the 
study. The CTA must be signed before the start of the study. If there are differences between 
the CTA and the Protocol regarding certain rights and obligations the CTA is the prevailing 
document. Indemnification is covered by the CTA between the sponsor and the Institution. 
OxThera has civil liability insurance, which covers this study in all participating countries. 

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18 CONFIDENTIALITY, INTELLECTUAL PROPERTY AND 
PUBLICATION POLICY 
Investigator’s, Institution’s and OxThera IP AB’s obligations regarding intellectual property, 
confidentiality and publication are described in detail in the Clinical Trial Agreement. They 
can be summarized as follows; 
All information (whatever form) disclosed by OxThera to Institution, or generated pursuant to 
this study, shall be deemed to be confidential information. Except as required by applicable 
law, Institution shall not use or disclose to any party OxThera 's confidential information 
received pursuant to this study or otherwise, without the prior written consent of OxThera. All 
data generated or arising from the performance of the study shall be the exclusive property of 
OxThera. 
It is intended to publish the results of the study as a whole once all subjects have completed 
the study and the study has been analysed. If there is a publication, the Investigator that has the 
highest number of treated subjects will be the lead author, unless otherwise agreed. The 
investigator may not publish the results of their cohort of subjects until the full study has been 
submitted for publication. The investigator may not submit for publication or present the results 
of this study without allowing OxThera 30 days in which to review and comment on the pre-
publication manuscript. The investigator may not submit the results of the study for publication 
without the prior consent of OxThera, unless the review period has passed and there has been 
no reaction from the sponsor. 

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19 CHANGES TO THE STUDY PROTOCOL 
The investigator should not implement any deviation from or changes to the protocol without 
agreement with the sponsor and prior review and documented approval from the IEC and 
Regulatory Authorities, except where necessary to eliminate an immediate hazard to the 
subjects. All changes to the final study protocol must be documented in a written protocol 
amendment. 
 
 

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20 REFERENCES 
Aggarwal KP et al. Nehprolithiasis: Molecular Mechanism of Renal Stone Formation and the 
Critical Role Played by Modulators. BioMed Res Int Vol 2013; Article ID 292953. 
Boyce AM et al. Ultrasound is superior to computed tomography for assessment of 
medullary nephrocalcinosis in hypoparathyroidism. J Clin Endocrin Metab, 2013; 98: 989-
994.  
Cochat, P. et al. Epidemiology of primary hyperoxaluria type 1, Nephrol Dial 
Transplantation, 1995; 10(Suppl 8), pp. 3–7. 
Cochat P and Rumsby G. Primary Hyperoxaluria, N Engl J Med 2013; 369:649-58. 
Hatch M et al., New Enzymic Method for Serum Oxalate Determination. Clin Chem, 1977; 
23(1):76-7.  
Hatch M., Spectrophotometric determination of oxalate in whole blood. Clin Chim Acta, 
1990; 193:199-202. 
Hatch M and Freel RW. Intestinal transport of an obdurate anion: oxalate. Urol Res, 2005; 
33:1-16. 
Hatch M. et al. Enteric ox elimination is induced and ox is normalized in a mouse model of 
PH following intestinal colonization with Oxalobacter. AJPGLP, 2011; 300: G461-G469 
Hoppe B et al. Oxalobacter formigenes: a potential tool for the treatment of primary 
hyperoxaluria type 1. Kidney Intl, 2006; 70:1305–11. 
Hoppe B, Beck B and Milliner D. The Primary Hyperoxalurias. Kidney Intl, 2009; 75: 1264-
71. 
Hoppe B et al. Reduction of plasma oxalate levels by oral application of Oxalobacter 
formigenes in 2 patients with infantile oxalosis. Am J Kidney Dis, 2011; 58(3):453-5. 
Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol, 2012; 8:467-75.  
Lagies R et al. Apical Sparing of Longitudinal Strain, Left Ventricular Rotational 
Abnormalities, and Short-Axis Dysfunction in Primary Hyperoxaluria Type 1. Circulation: 
Heart Failure. 2013; 6: e45-e47. 
Lagies, R. et al. Subclinical myocardial disease in patients with primary hyperoxaluria and 
preserved left ventricular ejection fraction: a two-dimensional speckle-tracking imaging 
study, Pediatric Nephrology (Berlin, Germany), 2019; 34(12), pp. 2591–2600 
Levey AS et al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 
2009, 150(9): 604–612. 
Ng DK et al. Combination of pediatric and adult formulas for valid glomerular filtration rate 
estimates in young adults with a history of pediatric chronic kidney disease. Kidney Intl, 
2018; 94(1): 170-177. 
Pape, L. et al. Oxalobacter formigenes treatment combined with intensive dialysis lowers 
plasma oxalate and halts disease progression in a patient with severe infantile oxalosis, 
Pediatric Nephrology 2020, 35: 1121-1124. 
Pascual E and Sivera F, Time required for disappearance of urate crystals from synovial fluid 
after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis. 
2007; 66:1056-8. 

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Rare Kidney Stone Consortium (2013) Primary Hyperoxaluria. Available at: 
https://www.rarekidneystones.org/hyperoxaluria/physicians.html (Accessed: 24 September 
2019). 
Ratitch B, OKelly, Tosiello M. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharma Stat. 2013; 12: 337-47. 
 
Sivaguru M et al. Geobiology reveals how human kidney stones dissolves in vivo. Scientific 
Reports 2018; 8: 13731 (DOI:10.1038/s41598-018-31890-9). 
Schwartz GJ et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 
2009, 20:629–637. 
Stewart CS, Duncan SH and Cave DR. Oxalobacter formigenes and its role in oxalate 
metabolism in human gut. FEMS Microbiol Lett 2004; 230:1-7. 
van der Hoeven SM et al. Primary hyperoxaluria Type 1, a too often missed diagnosis and 
potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. 
Nephrol Dial Transplant 2012, 27: 3855-3862.s 
Zhao F et al., Predictors of Incident ESRD among Patients with Primary Hyperoxaluria 
Presenting Prior to Kidney Failure.  Clin J Am Soc Nephrol. 2016; 11(1):119-26. 
 

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21 APPENDICES 
Appendix 1: Study protocol approval by investigator 
 
 

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Appendix 1: Study protocol approval by investigator 
 
 
Protocol number: OC5-DB-02 
 
Protocol Date:  
08 January 2021 
 
Protocol Version: 11 
 
 
Study title: 
A phase III double-blind, randomized study to evaluate the long-term 
efficacy and safety of Oxabact in patients with primary hyperoxaluria 
 
Sponsor: 
OxThera Intellectual Property AB 
 
Regeringsgatan 111 
SE-111 39 Stockholm   
 
Sweden 
 
 
I, the undersigned, have read and understand the protocol specified above, and agree on the 
contents. The Study Protocol, the Clinical Trial Agreement/ Financial Agreement, and GCP 
Guidelines will serve as a basis for co-operation in this study. 
 
 
Investigator: 
 
 
Affiliation: 
 
 
 
 
 
 
 
 
Signature: 
 
 
Date: 
 
 
 
DD –MMM – YYYY