A Phase 2 Open-label Multi-centre Study to Evaluate the Efficacy and Safety of Oxabact® to Reduce Plasma Oxalate in Subjects With Primary Hyperoxaluria Who Are on Dialysis
Phase: PHASE2
Conditions: Primary Hyperoxaluria
Sponsor: OxThera

Protocol OC5-OL-01, Confidential 
 
 
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Clinical Study Protocol 
Oxalobacter formigenes (Oxabact®) 
 
A phase 2 open-label multi-centre study to evaluate the efficacy and 
safety of Oxabact® to reduce plasma oxalate in patients with primary 
hyperoxaluria who are on dialysis 
 
Protocol Number 
OC5-OL-01 
 
EudraCT Number 
2013- 004368-74 
 
Sponsor: 
OxThera Intellectual Property AB 
 
Regeringsgatan 111 
 
 SE-111 39 Stockholm 
 
Sweden 
 
Sponsor signee: 
Bastian Dehmel, MD, Chief Medical Officer 
 
 
Protocol Date:  
14 October 2019 
 
 
Protocol Version: 
12, including amendment XIII 
 
 
 
 
 
 
- 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. 
 
 

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Revision History 
Rev.: 
Description: 
Effective Date: 
000 
New document 
2013-10-14 
001 
Amendment I: 
• Addition of a new inclusion criterion; this details the 
minimum age of the patients (≥ 2 years) and that they 
they must be able to swallow the capsules or can use 
a gastric tube that allows for administration of the 
capsules. 
 
• Addition of a new exclusion criterion concerning 
inability to take study medication. 
 
• Clarification that patients may receive capsules 
through a gastric tube. 
 
• Information on the number of patients expected to be 
children in the study. 
 
• Information provided on the dose justification. 
 
• Information on the risks, burdens and expected 
benefit of Oxabact OC5 administration to patients. A 
benefit risk assessment now provided. 
 
• Clarification that children will not be treated with 
Oxabact OC5 until the 4-week safety data from at least 
two adult patients in the earlier OC5-DB-01 study has 
been reviewed and raises no safety concerns. 
 
• Clarification of the maximum volume of blood draws 
at each visit. 
 
• Minor non-substantial corrections and/or 
clarifications  
2014-02-14 
002 
Amendment II – US specific 
2014-03-26 
003 
Amendment III – US specific 
2014-05-09 
004 
Amendment IV: 
• After the follow-up period, patients will be offered to 
continue on study drug treatment until 
transplantation. During this period of time, monthly 
clinic visits will be performed including plasma 
2014-10-21 

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oxalate sampling and safety labs. Stool samples will 
be taken every 8th week.  
• Addition of a secondary endpoint to evaluate the 
efficacy and safety of long-term treatment for 
patients who continue on study drug after the follow-
up period. 
• Speckle Tracking Echocardiography will be 
performed at screening or week 14 visit and 
repeated every 6 months during the continued 
treatment period. Speckle Tracking 
Echocardiography will be done at sites that routinely 
do this examination and will be evaluated for 
clinically significant changes during the study period.  
• Addition of analysis of Calcium, Magnesium, Citrate 
and Creatinine for 24h urine samples – only for 
patients in the sub-study (US). 
• Additional information regarding current clinical 
studies added in the section about clinical experience 
with Oxabact.  
005 
Amendment V  
• The length of the continued treatment period has 
been limited to a maximum of 12 months.  
• An individual benefit/risk assessment will be done 
by the investigator before the start of the continued 
treatment and every third month during the 
continued treatment period.  
• Section 4.6 Overall risk and benefit assessment has 
been updated. 
2014-12-14 
006 
Amendment VI  
• Country specific amendment for France.  
2015-02-20 
007 
Amendment VII 
• The timeline for evaluation of the primary endpoint 
(change in plasma oxalate from baseline) has been 
amended. 
• The timeline for evaluation for some of the secondary 
endpoints (safety and change in number of O. 
formigenes in faeces) has been amended. 
• The length of the continued treatment period has 
been extended by an additional 12 month period (i.e. 
to a maximum of 24 months). 
2016-03-08 

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• The efficacy results from the OC5-DB-01 study have 
been included. 
• Safety data has been updated for the OC5-DB-01 and 
OC5-OL-01 studies. 
• In addition to the analyses of total plasma oxalate by 
the AMC laboratory, the Bonn laboratory will analyse 
free plasma oxalate using a standard plasma oxalate 
Ion Chromatography (IC) method. 
008 
Amendment VIII 
• Updated Emergency Contact Information in Table 1. 
• Updated contact information for reporting of SAEs in 
section 11.4  
2016-05-31 
008 
Amendment IX  
• Added oxalate removal sub-study to Secondary 
Objectives in synopsis which had been omitted by 
mistake. 
• Correction of inclusion/exclusion criteria regarding 
swallowing capsules to remove the 6 weeks time-
frame.  
• Clarifying the analysis of plasma oxalate by IC 
method at local lab or Central lab in Bonn.  
• Revision of section 9 Study Drug Materials and 
Management to reflect a change of number of 
capsules in each vial from 18 to 14 capsules per vial.  
• Updated data on reported Adverse Events in section 
11.5.1.2. 
• Minor corrections and administrative changes.  
2016-09-20 
009 
Amendment X 
• The length of the continued treatment period has 
been extended by an additional 12-month period (i.e. 
to a maximum of 36 months). 
• Coordinating investigator has been changed to Prof 
Hoppe, UKB, Bonn, Germany. 
• Updated safety results for the study.  
• Minor corrections and administrative changes. 
2017-04-04 
010 
Amendment XI  
• Clarified that the primary endpoint will evaluate total 
plasma oxalate values.  
2017-11-24 

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• Added analysis of change in free plasma oxalate 
values as a secondary endpoint.  
• Visit frequency for continued treatment year three 
changed from once monthly to once every third 
month.  
• Removed sub-study on oxalate removal, since no 
patients have been included into the sub-study.  
• Revised exclusion criteria 11 and section 8.2.2 
Prohibited medications to allow for standard of care 
vitamin supplements for patients on dialysis.  
• An interim analysis will be done to analyse results 
from the first 12 months of continued treatment.  
• A transition from 14 capsules per vial to 18 capsules 
per vial will be done during 2018, to include some 
overage medication in each vial.  
• Clarification of the stability period for study drug 
stored in refrigerator.  
• Available local lab results for free plasma oxalate 
before effective date of Amendment VII will be 
captured retrospectively (see section 10.1) and 
included in the analysis.  
• Revised description of parameters to be evaluated 
for Speckle Tracking Echocardiography and 
traditional echocardiography. STE and traditional 
echocardiography evaluations performed before the 
effective date of this amendment will be re-evaluated 
to capture and analyse the same parameters.  
• Updated safety information in section 11.5.1.2. 
• Minor administrative and corrective changes.  
 
011 
Amendment XII 
• Final visit after completion of year 3 has been 
corrected from week 152 to week 156. 
• Central reading of echocardiography examinations 
has been added. 
2018-01-18 
012 
Amendment XIII 
• Information on the ongoing studies OC5-DB-02 and 
OC5-OL-02 was added to section 4.4 (including Table 
3), 4.6.2, 4.6.3 and 4.6.4. 
• Information on current study updated in Table 3. 
2019-10-14 

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• Information on another compassionate use patient 
was added to section 4.4.1.3. 
• Clarification in section 6.1 to add “dry weight” as part 
of dialysis regimen monitoring. 
• Removal of the term “pre-dialysis” and addition of a 
clarification of the sampling time-point in inclusion 
criteria (section 7.1), primary endpoint /efficacy 
parameters (section 10) and throughout the 
document. 
• Addition of transplantation to section 7.3 as an 
explicit reason for withdrawal. 
• Update of section 11.1 to include definition of events 
that are not to be reported as AEs. The update is 
done to harmonise with the protocols of studies OC5-
DB-02 and OC5-OL-02. 
• Update of section 11.5.1.1 and 11.5.1.2 to add 
information on the other ongoing studies OC5-DB-02 
and OC5-OL-02. 
• Update of section 11.5.1.2 to refer to Investigator 
Brochure, to harmonise with the protocol of the OC5-
OL-02 study. 
• Addition of interim analysis at 24 months of 
continued treatment to section 12.1 and to the 
Synopsis. 
• Change of coordinating investigator implemented. 
• Minor corrections and administrative changes.  
 
 

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Procedures in Case of Emergency 
 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Telephone number 
Fax number 
Drug Safety Physician/ 
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 Intellectual Property AB 
Name of Investigational Product: 
Oxabact® (OC5) 
Name of Active Ingredient: 
Oxalobacter formigenes, strain HC-1 
Title of Study:  
A phase 2, open-label, multi-centre study to evaluate the efficacy and safety of OC5 to 
reduce plasma oxalate in patients with primary hyperoxaluria who are on dialysis. 
Coordinating Investigator: 
Dr. Gesa Schalk, Universitätsklinikum Bonn, Germany. 
Participating countries and number of sites: 
The study will be conducted in one site in Germany. 
Studied period:  
Estimated date first patient enrolled: Q2 2014 
Estimated date last patient completed: Q1 2020. After the first 14 weeks of the study, 
patients will be offered to continue on study drug for up to 36 months or until 
transplantation.  
Phase of development: 2 
Objectives:  
Primary: 
o To evaluate the efficacy of OC5 to reduce total plasma oxalate levels during 
OC5 treatment in patients with Primary Hyperoxaluria (PH) who are on 
dialysis. 
Secondary: 
o To evaluate the efficacy of OC5 to reduce free plasma oxalate levels during 
OC5 treatment in patients with Primary Hyperoxaluria (PH) who are on 
dialysis. 
o To evaluate the safety of OC5 in patients with PH who are on dialysis. 
o To evaluate changes in number of O. formigenes in faeces following 
administration of OC5. 
o To evaluate effect of stopping OC5 treatment for 4 weeks after the first 6 
weeks of treatment.  
o To evaluate results from Speckle Tracking Echocardiography and traditional 
echocardiography.  

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Methodology:  
This open-label study will evaluate the safety and efficacy of OC5 in patients with PH 
who are on dialysis. Patients will initially be treated for 6 weeks with OC5. The study 
patients will be monitored for 4 weeks prior to initiation of study medication, as well 
as 4 weeks of follow-up after termination of study medication. If the patient, in the 
investigator’s opinion, has a positive effect of the study drug, patients will be offered 
to continue treatment with study drug after the 4-week follow-up period until 
transplantation (maximum length of the continued treatment period will be 36 
months). The investigator should confirm that the benefit/risk assessment for the 
individual patient is considered to be positive and that there are no complications or 
adverse events that could adversely affect the benefit/risk ratio. A repeated 
benefit/risk assessment for the patient will be done and documented every three 
months throughout the continued treatment period. 
Patients will be on a stable dialysis regimen. This could be only haemodialysis (HD), 
only peritoneal dialysis (PD) or combined HD and PD. The choice of dialysis regimen 
will be decided upon by the investigator and individualized to remove adequate 
oxalate to minimise the risk for systemic oxalosis. The PD regimen (number of 
days/week, hours per treatment, volume of dialysis buffer) and HD regimen (number 
of days/week; hours per treatment; blood and dialysate flow rates; and HD 
membrane) will be maintained for the duration of the study. This will be monitored 
and recorded by measuring volume of spent dialysate from HD and PD and 
quantifying dialysis dose of each HD session in terms of Kt/V measurement using an 
online clearance monitor. 
The plasma oxalate levels (the primary end point of this study) will be measured at 
weeks 2, 4, 6, 8, 10, 12, 14 during the first 14 weeks of the study, monthly throughout 
years 1 and 2 in the continued treatment period and every third or fourth month 
throughout year 3 of the continued treatment period (see illustrations of the study 
design below). A blood sample will be obtained after two consecutive days of dialysis 
on the preceding days but prior to the dialysis session on the day of sampling.  
Faecal samples will be collected at weeks 4, 10, 14 during the first 14 weeks of the 
study, every 2 months throughout years 1 and 2 in the continued treatment period 
and every 3-4 months throughout year 3 of the continued treatment period. Faecal 
samples are analysed for determination of O. formigenes. Safety evaluation will 
include safety labs at weeks 0, 4, 10, 14 during the first 14 weeks of the study, 
monthly throughout years 1 and 2 in the continued treatment period and every 3-4 
months throughout year 3 of the continued treatment period. Adverse events will be 
monitored throughout the study.  
Speckle Tracking Echocardiography will be performed during baseline if possible. If 
the examination could not be performed during baseline, an effort will be made to 
perform the Speckle Tracking Echocardiography before start of continued treatment 
(if applicable). The procedure will be repeated every 6 months throughout the 
continued treatment period, if possible.  

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Illustration of the study design – the first 14 weeks of the study 
For patients continuing on treatment with study drug after week 14, monthly clinic 
visits will be performed including plasma oxalate sampling and safety labs during 
years 1 and 2. Stool samples will be taken every 8th week. During year 3 of the 
continued treatment period clinical visits and collection of stool samples will be done 
every third or fourth month. 
 
 
 
 
 
 
 
 
 

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Illustration of the study design - continued treatment Year 1 and 2 
Illustration of the study design - continued treatment Year 3 
Number of patients (planned):  
Approximately 6 to 12 patients will be enrolled in the study, it is estimated that 2 of 
these patients will be children. 

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Diagnosis and main criteria for inclusion:  
Main Inclusion Criteria: 
1. Signed informed consent (as applicable for the age of the patient). An 
appendix to the informed consent form will be signed by patients continuing 
on treatment after week 14.  
2. Male or female patients ≥ 2 years of age. Patients have to be able to swallow 
size 4 capsules twice daily, or use a gastric tube that allows for administration 
of size 4 capsules.  
3. A diagnosis of PH (as determined by standard diagnostic methods). 
4. Patient should be on a stable dialysis regimen for at least two weeks before 
baseline.  
5. Plasma oxalate ≥40 micromole/L prior to the dialysis session.  
6. Patients receiving vitamin B6 must be receiving a stable dose for at least 3 
months prior to screening and must remain on the stable dose during the 
study. Patients not receiving vitamin B6 at study entry must be willing to 
refrain from initiating vitamin B6 during study participation. 
Main Exclusion Criteria: 
7. Inability to swallow size 4 capsules twice daily, or using a gastric tube not 
suited for administration of size 4 capsules via the tube. 
8. Ongoing treatment with immunosuppressive medication. 
9. 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. 
10. Use of antibiotics to which O. formigenes is sensitive, including current 
antibiotic use, or antibiotics use within 14 days of initiating study medication. 
11. Current treatment with a separate ascorbic acid preparation. Standard of care 
vitamin supplement for patients on dialysis are allowed.  
12. Pregnancy. 
13. Women of childbearing potential who are not using adequate contraceptive 
precautions.  Sexually active females, unless surgically sterile or at least 2 
years post-menopausal, must be using a highly effective contraception 
(including oral, transdermal, injectable, or implanted contraceptives, IUD, 
abstinence, use of a condom by the sexual partner or sterile sexual partner) 
for 30 days prior to the first dose of OC5 and must agree to continue using 
such precautions during the clinical study. 
14. Presence of a medical condition that the Investigator considers likely to make 
the patient susceptible to adverse effect of study treatment or unable to 
follow study procedures.  
15. Participation in any study of an investigational product, biologic, device, or 
other agent within 30 days prior to the first dose of OC5 or not willing to 
forego other forms of investigational treatment during this study. 
Investigational product, dosage and mode of administration:  
The study drug consists of OC5. The dose will be administrated orally with breakfast 
and dinner as one enteric-coated capsule two times per day. For patients using a 
gastric tube the capsules may be administered through the tube. The dose will be 
NLT ≥1E+09 colony forming units (CFU) per capsule.  

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Duration of treatment:  
Patients will initially be treated for 6 weeks with OC5. Prior to initiation of study 
medication, the patients will be monitored for 4 weeks. After termination of study 
medication for the 6-week period the patients will be followed for a 4 weeks follow-
up period.  
After the end of the 4 weeks follow-up period, the patients will be offered to continue 
treatment until transplantation. The maximal length of the continued treatment 
period will be 36 months. A repeated benefit/risk assessment for the patient will be 
done and documented every three months throughout the continued treatment 
period. 
Criteria for evaluation: 
Efficacy: 
Primary endpoint: 
- 
Change in plasma oxalate (total plasma oxalate) level during OC5 treatment, 
compared with baseline. 
Secondary endpoints: 
- 
Change in plasma oxalate (free plasma oxalate) level during OC5 treatment, 
compared with baseline. 
- 
Change in plasma oxalate (total plasma oxalate) values from week 10 to week 
14, following the 4 week off-treatment period. 
- 
Change in number of O. formigenes in faeces during OC5 treatment. 
- 
To evaluate results from Speckle Tracking Echocardiography and traditional 
echocardiography.  
Safety: 
- 
Adverse events (AEs), haematology, clinical chemistry, urinalysis. 
Statistical methods: Evidence for efficacy will be provided as the combined 
evaluation of individual case studies. 
Efficacy: The primary endpoint, change in total plasma oxalate from baseline, will be 
evaluated over time for each patient. Plasma oxalate levels will be measured on a 
monthly basis for the initial part of the study and the first 24 months of the 
continued treatment period, and once every three or four months for the last 12 
months of the continued treatment. The duration of treatment will depend on the 
individual treatment time for each patient. All secondary endpoints will be analysed 
using the same methodology.  
Two interim analyses will be performed: The first analysis will be based on patients 
who complete the first year of continued treatment.  The second interim analysis will 
be based on all study data obtained up to 24 months. Both interim analyses will 
evaluate all captured efficacy and safety parameters. 
The study involves a small number of patients and natural history data on changes in 
total and free plasma oxalate for this population is limited.  Response to treatment is 
likely to vary depending on the baseline plasma oxalate level, individual hepatic 
oxalate production and age of each patient. Accordingly, the sample size is not based 
on assumptions of efficacy outcome and statistical power. Any inferences from the 
data will be based on clinical relevance rather than statistical significance. 

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Safety: The safety will be summarised using descriptive statistics based on 
frequency, seriousness and severity of treatment emergent AEs. Clinically relevant 
changes in safety laboratory parameters will also be summarised. 
 
 
 

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2 TABLE OF CONTENTS 
1 
Synopsis ....................................................................................................................................... 9 
2 
Table of Contents .................................................................................................................. 16 
2.1 
List of Tables ................................................................................................................................ 18 
2.2 
List of figures ............................................................................................................................... 18 
3 
List of abbreviations and definitions of terms ........................................................... 19 
4 
Introduction ............................................................................................................................ 20 
4.1 
Primary hyperoxaluria ............................................................................................................ 20 
4.1.1 
Aetiology, clinical features and epidemiology .......................................................................... 20 
4.1.2 
Unmet medical need ............................................................................................................................ 20 
4.2 
Oxabact® ........................................................................................................................................ 21 
4.3 
Oxabact® treatment for PH patients ................................................................................... 21 
4.4 
Clinical experience with Oxabact® ....................................................................................... 22 
4.4.1 
Clinical experience in PH patients on Dialysis .......................................................................... 26 
4.4.2 
Clinical Experience with Oxabact® OC5 in PH patients with maintained renal 
function (results from the OC5-DB-01 study) .......................................................................................... 28 
4.5 
Rationale for current phase 2 study.................................................................................... 30 
4.5.1 
Overall objective ................................................................................................................................... 30 
4.5.2 
OC5 development ................................................................................................................................. 31 
4.5.3 
Dose justification .................................................................................................................................. 32 
4.6 
Overall risk and benefit assessment ................................................................................... 33 
4.6.1 
Burden ....................................................................................................................................................... 33 
4.6.2 
Risk threshold ........................................................................................................................................ 33 
4.6.3 
Benefits ..................................................................................................................................................... 34 
4.6.4 
Benefit:Risk Assessment .................................................................................................................... 35 
5 
Trial Objectives and purpose............................................................................................ 36 
5.1 
Primary objective ...................................................................................................................... 36 
5.2 
Secondary objectives ................................................................................................................ 36 
6 
Investigational plan ............................................................................................................. 36 
6.1 
Overall study design and plan ............................................................................................... 36 
6.2 
Schedule of assessments ......................................................................................................... 39 
6.2.1 
Screening .................................................................................................................................................. 43 
6.2.2 
Baseline ..................................................................................................................................................... 43 
6.2.3 
Treatment period – the first 6 week treatment period (study week 5-10) .................. 44 
6.2.4 
Post treatment period – 4 weeks without study drug (study week 11-14) ................. 44 
6.2.5 
Continued treatment period ............................................................................................................ 45 
6.3 
Specimen collection at patient’s homes ............................................................................. 45 
6.4 
Diet .................................................................................................................................................. 45 
7 
Selection and Withdrawal of patients ........................................................................... 46 
7.1 
Patient inclusion criteria ........................................................................................................ 46 
7.2 
Patient exclusion criteria ........................................................................................................ 46 
7.3 
Patient withdrawal criteria .................................................................................................... 47 
8 
Treatment of patients .......................................................................................................... 47 
8.1 
Description of study treatment ............................................................................................. 47 
8.2 
Concomitant medications ....................................................................................................... 48 
8.2.1 
Concomitant treatment with vitamin B6 .................................................................................... 48 
8.2.2 
Prohibited medications ...................................................................................................................... 48 
8.3 
Treatment compliance ............................................................................................................. 48 

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9 
Study drug Materials and Management ........................................................................ 49 
9.1 
Study drug ..................................................................................................................................... 49 
9.2 
Study drug packaging and labelling .................................................................................... 49 
9.3 
Study drug storage ..................................................................................................................... 49 
9.4 
Study drug accountability, handling and disposal ......................................................... 49 
10 Assessment of Efficacy ........................................................................................................ 50 
10.1 
Plasma oxalate ............................................................................................................................ 50 
10.2 
Quantification of O. formigenes ............................................................................................. 51 
10.3 
Speckle Tracking Echocardiography and Traditional Echocardiography ............ 51 
11 Assessment of Safety ............................................................................................................ 51 
11.1 
Definition of Adverse Events ................................................................................................. 52 
11.2 
Relationship to study drug ..................................................................................................... 53 
11.3 
Recording Adverse Events ...................................................................................................... 54 
11.4 
Reporting Adverse Events ...................................................................................................... 54 
11.5 
Anticipated Adverse Events ................................................................................................... 55 
11.5.1 
Review of available data ............................................................................................................... 55 
11.5.2 
Systemic infections due to O. formigenes ............................................................................... 58 
11.5.3 
Elevated levels of plasma formate ............................................................................................ 59 
11.6 
Laboratory safety measurements ........................................................................................ 59 
12 Statistics ................................................................................................................................... 60 
12.1 
Statistical methods .................................................................................................................... 60 
13 Direct access to source data/documents ...................................................................... 61 
14 Quality control and quality assurance .......................................................................... 61 
14.1 
Monitoring and audits .............................................................................................................. 61 
14.2 
Site personnel.............................................................................................................................. 61 
15 Ethics and regulatory requirements .............................................................................. 62 
15.1 
Ethics review ............................................................................................................................... 62 
15.2 
Ethical conduct of the study ................................................................................................... 62 
15.3 
Written informed consent ...................................................................................................... 62 
15.4 
Regulatory requirements ........................................................................................................ 63 
16 Data handling and recordkeeping .................................................................................. 63 
16.1 
Case report forms ...................................................................................................................... 63 
16.2 
Retention of records ................................................................................................................. 63 
16.3 
Protection of personal data .................................................................................................... 63 
17 Financing, indemnification and insurance .................................................................. 64 
18 Confidentiality, intellectual property and publication policy .............................. 64 
19 Changes to the Study Protocol .......................................................................................... 64 
20 References ............................................................................................................................... 65 
21 Appendices .............................................................................................................................. 66 
 
 
 

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2.1 List of Tables 
Table 1: 
Emergency Contact Information ................................................................ 8 
Table 2: 
Abbreviations and specialist terms ....................................................... 19 
Table 3:  
Summary of clinical studies ................................................................... 23 
Table 4: 
Schedule of assessments – the first 14 weeks of the study ................. 40 
Table 5:  
Schedule of assessments – continued treatment Year 1 and 2, .......... 41 
Table 6  
Schedule of assessments – continued treatment Year 3…………..….…..42 
Table 7:  
Details of the study drug in the OC5-OL-01 study ............................... 49 
Table 8:  
Summary of all adverse events in OC5-DB-01 (safety analysis set). .. 56 
Table 9:  
Summary of types of adverse events experienced in OC5-DB-01 
(Safety analysis set). ............................................................................... 57 
 
 
 
 
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). .......................................................................... 26 
Figure 2: Follow up of plasma oxalate levels in patient 1 during treatment with 
Oxalobacter formigenes. ......................................................................... 27 
Figure 3: Follow up of plasma oxalate levels in patient 2 during treatment with 
Oxalobacter formigenes .......................................................................... 28 
Figure 4: 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. ............................................................................................ 29 
Figure 5: Potency of OC5 compared to OC3. ............................................................ 32 
Figure 6: Study design for OC5-OL-01 - the first 14 weeks of the study. .............. 38 
Figure 7: Study design for OC5-OL-01 continued treatment period Year 1 and 2
 .................................................................................................................. 38 
Figure 8: Study design for OC5-OL-01 continued treatment period Year ….…...…39 
 
 

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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 
CAPD 
Chronic Ambulatory Peritoneal Dialysis. 
CCPD 
Continuous Cycling Peritoneal Dialysis 
CFU 
Colony Forming Units 
CRF 
Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ESRD 
End-Stage Renal Disease 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GRHPR 
Glyoxylate reductase / hydroxypyruvate reductase 
HD 
Haemodialysis 
HOGA 
4‑hydroxy‑2-oxoglutarate aldolase 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
NLT 
Not Less Than 
NMT 
Not More Than 
OC3 
Old Investigational Drug, evaluated in earlier clinical 
studies. 
OC5 
Investigational Drug 
PD 
Peritoneal Dialysis 
PH 
Primary Hyperoxaluria 
PI 
Principal Investigator 
The investigator who leads the study conduct at an 
individual study centre.   
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 

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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 -hydroxy-
pyruvate 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.1 
All types of PH are characterised by severe hyperoxaluria. Oxalate cannot be 
metabolised by human cells and is primarily eliminated through the kidneys and the 
gastrointestinal tract 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) and such high oxalate concentration levels 
damage the renal parenchymal cells both as free oxalate and as calcium-oxalate 
crystals.1 In addition to calcium-oxalate deposition, chronic hyperoxaluria is associated 
with parenchymal inflammation and interstitial fibrosis.1,2 
In PH, marked hyperoxaluria is present from birth. There is however a marked 
interfamilial as well as intrafamilial heterogeneity of disease expression, where the 
individual hepatic oxalate production and time for exposure to high oxalate (age) are 
important factors.3 The majority of patients are symptomatic during childhood and 
mostly before 10 years of age. In some cases, however, the disease may go unrecognised 
until patients reach 30-50 years of age. Overall, the risk for end-stage renal disease 
(ESRD) is 50% by age of 15 and 80% by age 30. The median age at death is around 30.2 
PH is an ultra-rare disease with a prevalence for PH type I of 1-5 per million and an 
incidence rate of approximately 1 per 120 000 births in Europe. PH type I is the most 
common variant, accounting for 70-80% of all cases. Available prevalence and incidence 
rates may however be underestimated because of the diagnosis being delayed or 
overlooked.4 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. Patients with end stage 
renal disease receive dialysis while waiting for transplantation. So far dialysis has not 
been shown to overcome the problems of 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, metabolic bone disease, refractory anaemia, cardiomyopathy and 
cardiac conduction system abnormalities causing severe morbidity and mortality.1,2  
4.1.2 Unmet medical need 
The clinical management of PH patients is very challenging particularly when they reach 
ESRD. Once the patient reaches ESRD it is very difficult to achieve adequate removal of 
endogenous oxalate using the current dialysis techniques. Neither haemodialysis nor 

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peritoneal dialysis is able to keep pace with the endogenous production of oxalate. 
Accumulation of oxalate in plasma and in blood vessels start early and accumulation in 
extra-renal tissues starts when the local critical saturation point for plasma oxalate level 
is reached.5 Saturation limits ranging from 30-60 micromoles/L have been reported 
depending on the fluid composition in the local environment. Intensified five-hour 
sessions of haemodialysis for 5 or 6 days/week are often performed until 
transplantation.6 
A medical treatment, which can enhance or contribute to the removal of oxalate in 
addition to dialysis could be of immense importance in management of these patients. 
4.2 Oxabact® 
The active study drug Oxabact® consists of lyophilised O. formigenes strain HC1 in an 
enteric-coated capsule for oral administration. 
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.7 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.  
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, thereby potentially mobilising 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.8 Administration of the bacteria O. formigenes is 
proven to create a suitable 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 9 
Incremental secretion of oxalate into the gut can be maintained by constantly degrading 
the secreted oxalate with the help of O. formigenes in the 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 in ESRD. 

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4.4 Clinical experience with Oxabact® 
Five clinical studies in PH patients 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 placebo-controlled, double-blind randomised 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. 
Three studies are currently ongoing, all with the Oxabact® OC5 product: these include 
the current study (OC5-OL-01), a placebo-controlled, double-blind randomised phase III 
study (OC5-DB-02) and a single-arm, open-label extension study to the latter (OC5-OL-
02). For further details, please see Table 3. 
 
 
 

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Table 3: Summary of clinical studies 
 
 
Study 
Sites/Patients 
Study drug 
Outcome 
CTIxOC.002  
Phase I/II, open-label, non-
comparative. 
4 weeks treatment 
- 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.  
- Reduction in plasma oxalate in 
some patients on dialysis 
- No safety concerns 
CTIxOC.002 A 2-3  
Phase I/II, open-label, non-
comparative. 
4 weeks treatment 
- 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 lyophilised powder. 
Two capsules were given orally 
b.i.d. with meals. 
- Significant reduction in 
urinary oxalate in nearly all 
patients 
- No safety concerns 
OC3-DB-01  
Phase II/III, double-blind, 
placebo-controlled. 
24 weeks treatment 
- 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 lyophilised 
powder. One capsule was given 
orally b.i.d. with meals. 
- Post hoc analyses showed 
trends toward reduction in 
urinary oxalate 
- No safety concerns 
- Questionable 24-hour urine 
collections 
OC3-OL-01 
Open-label extension study, 
non-comparative. 
12 to 24 weeks treatment 
- 8 sites, n=37 
- PH type 1/2 
- 16 males, 21 females 
- Mean age 14, range 6-38 
OC3b**: Enteric coated 
capsule, containing 137 mg 
(NLT 1E+07 CFU) of lyophilised 
powder. One capsule was given 
orally b.i.d. with meals. 
- 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. 
24 weeks treatment 
- 3 sites, n=34 
- 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 lyophilised 
powder. One sachet, 
reconstituted with water and 
bicarbonate buffer, given orally 
b.i.d. before meals. 
- No trends towards reduction 
in urinary oxalate 
- No safety concerns 
- Improved 24-hour urine 
collections 

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OC5-DB-01  
Phase I/II, double-blind, 
placebo-controlled, multi-
centre 
8-10 weeks treatment 
– 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 lyophilised 
powder. 
One capsule was given orally 
b.i.d. with meals. 
 
 
– No significant difference for 
primary endpoint (urinary 
oxalate excretion) 
– Marked patient 
heterogeneity with 
indication that oxalate 
deposits may be dissolving 
in OC5-treated patients 
– Post hoc analyses identified 
a small, but statistically 
significant increase of 
oxalate excretion per 
creatinine excretion and a 
statistically significant 
correlation between change 
in plasma oxalate and 
change in Oxalobacter. 
– No safety concerns 
 
OC5-OL-01 (ongoing)  
Phase I/II, open-label, non-
comparative, multi-centre 
6 weeks + up to 36 months. 
– 1 site 
– 6-8 PH patients who are on 
dialysis 
OC5#: Enteric coated gelatine 
capsule, containing 80 mg (NLT 
1E+09 CFU) of lyophilised 
powder. 
One capsule given orally b.i.d. 
with meals. 
– Study ongoing 
– Study started in May 2014; 
12 patients received study 
drug, and 1 patient is still 
ongoing. Interim analysis 
findings show decreased 
plasma oxalate and signs of 
improved myocardial 
function in patients with 
low baseline cardiac 
function. 

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OC5-DB-02 (ePHex, ongoing) 
Phase III, double-blind, 
placebo-controlled, multi-
centre 52 weeks treatment 
– 11 sites 
– Plan to recruit 22 PH 
patients with eGFR 
<90ml/hr/1.73m2 and 
plasma oxalate ≥10µmol 
OC5#: Enteric coated gelatin 
capsule, containing 80 mg (NLT 
1E+09 CFU) of lyophilised 
powder. 
One capsule is given orally b.i.d. 
with meals. 
– Study ongoing 
– Study started in January 
2018 and is ongoing.  
16 patients have been 
randomised. 
OC5-OL-02 (ePHex-OLE, on-
going) 
Phase III, open-label, single-
arm, multi-centre, 104 weeks 
treatment 
– 11 sites 
– PH patients who completed 
ePHex will be offered 
participation 
– Planning to recruit 16 
patients 
OC5#: Enteric coated gelatin 
capsule, containing 80 mg (NLT 
1E+09 CFU) of lyophilised 
powder. 
One capsule is given orally b.i.d. 
with meals. 
– Study ongoing 
– Study started in April 2019 
– 4 patients have started 
open-label 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 on Dialysis 
 
4.4.1.1 CTIx.002: 
The first phase I/II study (CTIx.0002) was conducted in 9 patients using a frozen cell 
paste formulation of O. formigenes (OC2). Patients were given two doses of OC2 with 
two main meals per day for four weeks. Three PH I patients in ESRD who were 
undergoing dialysis were included in this study.10 
Figure 1 shows the change in plasma oxalate in these patients. Plasma oxalate 
measurements were made once a week from samples taken before the dialysis session. 
A substantial decrease in plasma oxalate was observed in two of the patients in ESRD 
and no safety concerns were observed10. In one of the patients (Female 21 years on HD) 
the treatment was prolonged to 5 weeks since the therapeutic effect was quite 
significant and this patient 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 patients 
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 patients. In this study, 
O. formigenes was lyophilised 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 patients 
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 patients. The plasma oxalate decreased by 26 μmol/L in the patient with end-
stage renal disease. OC3a treatment was well tolerated.  
4.4.1.3 Compassionate use 
Oxabact has also been evaluated during compassionate use in two 11-month-old girls 
with infantile oxalosis and ESRD (see Figure 2 and Figure 3). They received OC3b 
(administered together with esomeprazole via gastric 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 50 μmol/L (second treatment 
period) in patient 2.11 
Compassionate use of OC3b (broken capsules, 137-276 mg, mixed with a local 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). Recent analysis has shown that the buffer used at 
the time was not reconstituted properly and therefore was unsuitable for supporting 
survival of Oxalobacter in the stomach. 
OC3b and OC3 buffer were well tolerated and no serious side effects were reported 
during compassionate use.  
 
Figure 2: Follow up of plasma oxalate levels in patient 1 during treatment with 
Oxalobacter formigenes.  
 
 

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Figure 3: Follow up of plasma oxalate levels in patient 2 during treatment with 
Oxalobacter formigenes 
  
 
 
OC5 is currently being provided under named-patient use to a young girl with infantile 
oxalosis, in Germany. She developed end-stage renal disease shortly after birth and was 
treated with daily peritoneal and 3 times/week haemodialysis. Treatment with OC5 (in 
buffer solution) started in December 2017, when the child was 3 months old, and is 
ongoing (September 2019). The patient recently turned two years of age and is on the 
waiting list for a combined liver/kidney transplantation. According to the treating 
physician, there are clear indications that disease progression has slowed down during 
the course of treatment and that plasma oxalate levels have reduced and stabilised. OC5 
has been tolerated well by the patient. It is planned that the child will continue OC5 
Oxabact treatment until a combined liver/kidney transplantation can be performed. 
4.4.2 Clinical Experience with Oxabact® OC5 in PH patients with maintained 
renal function (results from the OC5-DB-01 study) 
The OC5-DB-01 study was a double-blind, randomised, 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 normalised to 1.73m2 
body surface area). The patients were randomised 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. 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 patients from 8 sites in Germany, France, and the United Kingdom were 
screened for inclusion in the study. 28 of these were randomised; 14 were randomised 
to receive Oxabact® and 14 randomised to receive placebo. All 28 patients 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 

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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 patients 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 patients aged 18 years or older 
than in the subgroup of patients 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 4: 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). 
 
 
≥18 years
<18 years
≥90 mL/min/1.73 m2
<90 mL/min/1.73 m2
With 
Without
>1.5 mmol/24 h/1.73 m2
≤1.5 mmol/24 h/1.73 m2
Full analysis set
-0.5
0
0.5
1
Difference (OC5-Placebo) in change in urinary oxalate excretion from baseline to Week 8 of treatment 
(mmol/24 h/1.73 m2)
Subject age 
Estimated glomerular 
filtration rate 
Vitamin B6 
therapy
Baseline urinary 
oxalate excretion 

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Despite a stratification of the two treatment groups (below/above 
1.5 mmol/24 h/1.73 m2), the patients in the OC5 group had more impaired renal 
function than the placebo patients. 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 patients in the OC5 group had a history of chronic renal 
failure, whereas no patients in the placebo group had been affected by this condition.   
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). 
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 patients with impaired renal function. The 
analyses also demonstrated that plasma oxalate concentration decreased as the number 
of O. formigenes increased in the OC5 treated patients, p=0.04. This suggests that the 
bacteria metabolise free oxalate that originates from plasma, thereby supporting that 
enteric elimination of oxalate has occurred.  
It is hypothesised that this reduction in free plasma oxalate disturbs the endogenous 
equilibrium between free plasma oxalate, plasma protein-bound oxalate and deposited 
oxalate and forces a dissolution of oxalate deposits in plasma-proteins and vessels, 
which 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 effective treatment leads to initially increased urinary urate 
excretion12. Because oxalate deposits are expected to be more pronounced in patients 
with impaired renal function, this hypothesis also explains why the effect of OC5 
treatment was greater in patients with more advanced kidney disease. A statistically 
significant decrease in urine output in the OC5-treated patients may also suggest that O. 
formigenes confers some beneficial effect on water reabsorption and urine 
concentrating-ability in the tubules of these patients. 
 
4.5 Rationale for current phase 2 study 
4.5.1 Overall objective 
The overall objective of this study is to study the efficacy of Oxabact® to reduce plasma 
oxalate in PH patients in ESRD who are undergoing dialysis.  Oxabact® has not been 
tested in a clinical trial designed for this patient population. Patients in ESRD who are on 
dialysis is a population with a significant unmet medical need for lowering the 
morbidity associated with oxalosis while the patients are waiting for a liver / kidney 
transplant. 
As described in section 4.4 although a positive efficacy outcome was seen in some of the 
ESRD patients enrolled in CTIxOC.002 (using the frozen cell paste OC2 formulation), the 
results from patients treated with the OC3b formulation in patients with maintained 
renal function were less substantial (Table 3: Summary of clinical studies). 

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OxThera has made significant improvements in the Oxabact® formulation to develop the 
OC5 product that has a one hundred times higher cell concentration and oxalate 
degrading activity as compared to OC3b. The new OC5 product has been evaluated in a 
multicentre double-blind controlled trial in PH patients with a GFR >40 ml/min/1.73 m2 
where urinary oxalate was the primary end-point (OC5-DB-01). In this current trial, 
OC5-OL-01, the OC5 product with higher concentration and faster recovery from the 
lyophilised state is tested in the PH patients in ESRD where plasma oxalate is the 
primary end-point.  
4.5.2 OC5 development 
OxThera has made changes to 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 rapid recovery of their 
oxalate degrading activity from the lyophilised state.  
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 to improve the capability of the 
cells to degrade oxalate at end of fermentation. Together with optimised excipients and 
relative amounts of these and cells, the product is now also better protected from the 
lyophilisation process, which in itself has also been improved. A significantly higher 
number of viable cells are recovered from the lyophilised state than previously 
recovered for the OC3b product. 
In addition, product-related analytical methods have been refined since the previous 
production process; Content (viable cell count, CFU/g) and Potency (oxalate degrading 
activity, mg oxalate degraded/capsule at 19h). The previous assays for OC3 did not 
differentiate very well between products with high or low potency. 
The higher concentration of viable cells and higher oxalate degrading activity in OC5 
allows for use of less lyophilised powder per dose. Thus, a smaller capsule, size 4 
instead of size 2, will be used.  
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 OC3b to better mimic the disintegration profile of a 
previous version of the product, OC3a.  
As can be seen in Figure 5, the OC5 material begins replicating much quicker than does 
the OC3b material.  In essence, with an improved cell bank, harvesting technique and 
freeze-drying strategy the quality of the product has been greatly improved.   
 

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Figure 5: Potency of OC5 compared to OC3. 
 
 
4.5.3 Dose justification 
Based on toxicity studies it should be within the NOAEL to administer up to 9 x 1011 CFU 
of OC5 twice daily to human patients. The OC5-OL-01 study will administer a 109 CFU 
twice daily dose to all patients. 
It needs to be taken into account that the oxalate degrading capacity, or potency, of 
Oxabact® is limited by the availability of endogenous oxalate. The daily plasma 
production of endogenous oxalate is 4–7 mmol/1.73m2 in PH 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 and no difference in safety is anticipated 
with varying oxalate degrading capacity due to the limited availability of endogenous 
oxalate. 
It is necessary to provide an exaggerated dose of Oxabact® to ensure 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. 
The OC5 drug product in the recent OC5-DB-01 (also dosed at NLT 109 CFU twice daily) 
study has been well tolerated with no safety concerns. 
 
 

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4.6 Overall risk and benefit assessment 
4.6.1 Burden 
Patients are requested to provide three faecal samples during the first 14 weeks of the 
study, one sample every second month during the first 24 months of the continued 
treatment period and one sample every third or fourth month for the final 12 months of 
the continued treatment period. Faecal samples will be collected at patients’ homes or at 
the clinic whichever is the most convenient for the patient. For samples collected at 
home, a designated courier will deliver collection kits and pickup collections at times 
agreed with the patients even during weekends if requested. 
Patients will attend clinical visits at eight times throughout the first 14 weeks of the 
study, once monthly during the first 24 months of the continued treatment period and 
once every third or fourth month for the final 12 months of the continued treatment 
period. This will involve time travelling to the hospital and the time required to see the 
investigator/study nurse. Since the patients are on dialysis, these visits may to a great 
extent be combined with regular visits to the clinic for dialysis treatment. Blood samples 
will be collected during the clinical visits for safety laboratory evaluations (four times 
during the first 14 weeks of the study, once monthly during the first 24 months of the 
continued treatment period and once every third or fourth month for the final 12 
months of the continued treatment period and for plasma oxalate analysis (seven times 
during the first 14 weeks of the study, once monthly during the first 24 months of the 
continued treatment period and once every third or fourth month for the final 12 
months of the study. Approximately 20 mL of blood will be needed for the safety lab 
sample and approximately 5 mL for the plasma oxalate sample.  
Study medication will be administrated orally with breakfast and dinner as one capsule 
two times per day, for 6 weeks and during the continued treatment period until the 
patient is transplanted or until a maximal length of the continued treatment period of 36 
months). The capsule size is quite small (size 4) and should be relatively easy to swallow 
even for younger patients. For patients using a gastric tube the capsules may be 
administered through the tube. The patients will be asked to complete a simple diary to 
record the study drug taken and any missed doses. 
Speckle Tracking Echocardiography and traditional echocardiography will be done 
during baseline and repeated every 6 months during the continued treatment period of 
maximum 36 months. The examination is non-invasive.  
4.6.2 Risk threshold 
Detailed information on the anticipated adverse events of the OC5-OL-01 study is 
outlined in section 10.5. In brief these potential risks may include: 
• Displacement of indigenous O. formigenes or changes in the normal gut 
microbiota 
• Infections 
• Elevated plasma formate 
• Gastrointestinal symptoms 
While the potential for these risks do 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 (OC3-DB-01 and OC3-DB-02) have also found that the OC3 product was safe and 

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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 is still favourable, as supported by the concluded bridging 
toxicology study (DP-1002). Twenty-eight consecutive days of twice daily oral 
administration by capsule of OC3 at 2E+08 CFU or OC5 at 9E+09 CFU 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, the current OC5-OL-01 study 
and the ongoing OC5-DB-02 and OC5-OL-02 studies indicate that the product is safe and 
well tolerated. No Oxabact® -related severe or serious adverse events have been reported 
so far in these on-going studies, see section 11.5.1. 
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. 
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 
patients. Furthermore, the patients will visit the clinic 8 times during the first 14 weeks 
of the study, once monthly during the first 24 months continued treatment and once 
every third or fourth month for the last 12 months of the continued treatment period for 
study specific visits in order to monitor adverse events and to make sure the patient 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. 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 nonclinical 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 people for time periods of 4 weeks to 12 months (with 
the majority of patients having been treated for 6 months). Administration of O. 
formigenes as a frozen cell paste, capsule or buffered powder for suspension was 
well tolerated in patients with primary hyperoxaluria. No SUSARs have been 
reported in any of these studies for Oxabact® and the product has had a favourable 
safety profile. 
The safety data available with the OC5 drug product from the completed OC5-DB-
01 study and the ongoing OC5-OL-01, OC5-DB-02 and OC5-OL-02 studies would 
also support the favourable safety profile. OC5 has been administered to 14 
patients in the OC5-DB-01 study and to 12 patients in the OC5-OL-01 study. Sixteen 
patients have been randomised in the ongoing OC5-DB-02 study. Four of these 
have entered the follow-up study OC5-OL-02 and are now receiving open-label 
Oxabact®. In OC5-DB-02, patients are randomised 1:1 to receive Oxabact® or 

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placebo; hence, it can be estimated that approximately 8 of the 16 randomised 
patients receive Oxabact®. No SUSAR has been reported in these studies for the 
Oxabact® product. Only 3 SAEs were reported in OC5-DB-01 and nine SAEs in OC5-
OL-01 to date. In OC5-DB-02, there have been 8 SAEs reported to-date; none of 
them was considered related to study drug. There have been no reported SAEs in 
the OC5-OL-02 study. The majority of AEs are mild and not related to the study 
drug.  
The OC5-OL-01 study should provide valuable information on the ability of the 
improved OC5 Oxabact® product to reduce plasma oxalate and confer clinical 
benefit in patients with PH who are on dialysis. A reduction of plasma oxalate may 
cause endogenous oxalate deposits to dissolve and thus treat systemic oxalate-
related complications. It will also generate further safety information on the 
product. Since PH patients on dialysis have a more severe form of the disease, they 
typically have higher plasma oxalate levels, more oxalate deposits and higher 
urinary oxalate levels (if not anuric) than PH patients with maintained renal 
function. OxThera believe that it is beneficial to have a 36-month continued 
treatment period for these patients. It may take some time to reduce the elevated 
plasma oxalate levels (which can be exceptionally high in these patients). 
Furthermore, the widespread oxalate deposits may start to dissolve once plasma 
oxalate levels decrease under saturation and prolongation of OC5 treatment may 
help in reducing the oxalate deposits in the body. 
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 oxalate crystallisation and currently there are limited treatments available for this 
disease.  This is particularly so for PH patients on dialysis who typically have extremely 
high plasma oxalate levels and widespread oxalate deposits in the body. The efficacy of 
Oxabact® in PH patients is still to be proven. It is hoped that improvements in the OC5 
formulation will result in a possible treatment for patients with PH.  
All nonclinical and clinical safety data to date indicate that Oxabact® has been well 
tolerated. There have been no SUSARs reported for Oxabact® in any clinical study with 
O. formigenes. Older studies with OC2 and OC3 drug product have been performed in 
over 80 patients 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. In addition, the 
improved product, OC5, has been administered to 14 patients in the OC5-DB-01 study 
and to 12 patients in the OC5-OL-01 study. Sixteen patients have been randomised in 
the ongoing OC5-DB-02 study, and 4 of these have entered the open-label extension 
study OC5-OL-02. Safety data from the completed OC5-DB-01 study and safety reporting 
of the on-going double-blind OC5-DB-02, the open-label OC5-OL-01 and the OC5-OL-02 
studies suggest that OC5 has a favourable safety profile and would not be expected to 
differ from that of the earlier OC3 drug product in terms of safety. 
Thus, based on the mechanism of action of OC5 (removal of free oxalate from plasma by 
enhancing the oxalate secretion from plasma to the gut), 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 

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benefit/risk evaluation of conducting this Phase II trial for treatment in patients with PH 
is considered favourable.  
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. 
5 TRIAL OBJECTIVES AND PURPOSE 
5.1 Primary objective 
o To evaluate the efficacy of OC5 to reduce total plasma oxalate levels during OC5 
treatment in patients with Primary Hyperoxaluria (PH) who are on dialysis. 
 
5.2 Secondary objectives 
o To evaluate the efficacy of OC5 to reduce free plasma oxalate levels during OC5 
treatment in patients with Primary Hyperoxaluria (PH) who are on dialysis. 
o To evaluate the safety of OC5 in patients with PH who are on dialysis. 
o To evaluate changes in number of O. formigenes in faeces following 
administration of OC5. 
o To evaluate effect of stopping OC5 treatment for 4 weeks after the first 6 weeks 
of treatment.  
o To evaluate results from Speckle Tracking Echocardiography and traditional 
echocardiography. 
6  INVESTIGATIONAL PLAN 
6.1 Overall study design and plan 
This study is an open label multi-centre study to evaluate the efficacy and safety of OC5 
(O. formigenes) to reduce plasma oxalate in PH patients on dialysis. It is hypothesised 
that daily administration of O. formigenes facilitates the secretion of endogenously 
produced oxalate from plasma to the GI tract. The enteric elimination of oxalate in 
addition to dialysis may help to lower the build-up of extra-renal oxalate in PH patients 
in ESRD. 
Patients will initially be treated for 6 weeks with OC5. The study patients will be 
monitored for 4 weeks prior to initiation of study medication, as well as 4 weeks of 
follow-up after termination of study medication. If the patient, in the opinion of the 
responsible investigator, has a positive effect of the study drug, patients will be offered 
to continue treatment with study drug after the 4-week follow-up period until 
transplantation (maximum length of the continued treatment period will be 36 months).  
The investigator should confirm that the benefit/risk assessment for the individual 
patient is considered to be positive and that there are no complications or adverse 
events that could adversely affect the benefit/risk ratio. A repeated benefit/risk 

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assessment for the patient will be done and documented every three months throughout 
the continued treatment period. 
Following screening and baseline evaluations eligible patients will receive Oxabact® 
twice daily for 6 weeks. The dose will be administrated orally with meals as one enteric-
coated capsule two times per day preferably with breakfast and dinner.  For patients 
using a gastric tube the capsules may be administered through the tube. The dose will 
be NLT 1E+09 CFU/capsule.   
Prior to enrollment patients will be on a stable dialysis regimen.  This could be only 
haemodialysis (HD), only peritoneal dialysis (PD) or combined HD and PD. The choice of 
dialysis regimen will be decided upon by the investigator and individualised to remove 
adequate oxalate to minimise the risk for systemic oxalosis. The PD regimen (number of 
days/week, hours per treatment, volume of dialysis buffer) and HD regimen (number of 
days/week; hours per treatment; blood and dialysate flow rates; and HD membrane) 
will be maintained for the duration of the study. This will be monitored and recorded by 
measuring volume of spent dialysate from HD and PD and quantifying dialysis dose of 
each HD session in terms of Kt/V measurement using an online clearance monitor. Each 
patient’s dry weight (target bodyweight after the dialysis session) will also be recorded. 
The total plasma oxalate (the primary end point of this study) will be measured at 
weeks 2, 4, 6, 8, 10, 12, 14, thereafter monthly for the first 24 months of continued 
treatment and every third or fourth month during the last 12 months of the continued 
treatment period (Figure 6 and Figure 7). A blood sample will be obtained after two 
consecutive days of completed dialysis regimen the preceding days, but prior to the 
dialysis session on the day of sampling.  The plasma samples will be processed at each 
clinical site and analysed for total plasma oxalate at the Academic Medical Center, 
Amsterdam and for free plasma oxalate at the local lab (Bonn University Clinical 
laboratory). 
Speckle Tracking Echocardiography and traditional echocardiography will be performed, 
if possible, at screening visit (+/- 1 month) or before start of continued treatment period 
(at visit week 14). Speckle Tracking Echocardiography and traditional echocardiography 
will then be repeated at week 24 in the continued treatment period and thereafter every 
6 months until end of treatment, if possible.  

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Figure 6: Study design for OC5-OL-01 - the first 14 weeks of the study. 
 
 
Figure 7: Study design for OC5-OL-01 continued treatment period Year 1 and 2 
 
 
 
 

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Figure 8: Study design for OC5-OL-01 continued treatment period Year 3 
 
 
 
Faecal samples will be collected for determination of O. formigenes at weeks 4, 10, 14, 
every 2 months throughout the first 24 months of the continued treatment period and 
every 3-4 months for the last 12 months of the continued treatment period. Faeces 
samples will be analysed at Institut fur Mikroökologie in Herborn, Germany. 
Safety evaluation will include safety labs at weeks 0, 4, 10, 14, monthly throughout the 
first 24 months of the continued treatment period and every 3-4 months for the last 12 
months of the continued treatment period. Physical examination will be done at weeks 
0, 4, 10, 14, every second month during continued treatment year 1 and 2 and every 3-4 
months during continued treatment year 3. Adverse events will be monitored 
throughout the study. Specimen samples will be analysed at a local laboratory. 
For the course of the study, the patients should be instructed to maintain their normal 
diet and fluid intake as prescribed under their standard clinical care.  
All patients will be monitored for safety and concomitant medication usage throughout 
the study period. 
Monitoring of adverse events, concomitant medication and compliance with the 
administration of study drug will be performed at least once monthly at each study visit 
for the first two years of continued treatment and at least every 3-4 months during the 
last year of the continued treatment period. 
6.2 Schedule of assessments 
The assessments to be performed during the study are described in Table 4: Schedule of 
assessments – the first 14 weeks of the study, Table 5: Schedule of assessments – 
continued treatment Year 1 and 2 and Table 6: Schedule of assessments – continued 
treatment Year 3. The procedures are further described in Sections 6.2.1– 6.2.5.
 

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Table 4: 
Schedule of assessments – the first 14 weeks of the study  
Study period: 
Screen
ing 
Baseline 
Treatment 
Post-treatment 
Week: 
-4 – 0 
“0” 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 
Clinic visit 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
Incl/Excl criteria1 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical exam 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
PH Med History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant med 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma oxalate 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Faeces 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Safety Labs2 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Treatment 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse events 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Speckle Tracking 
Echocardiography 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Eligibility criteria will be evaluated at Screening and after Baseline. A stable dialysis regimen should be 
maintained for 2 weeks before start of baseline (2 weeks before visit week 2) and during the whole study.  
2. Safety labs include: haematology analysis, clinical chemistry analysis and urinalysis and will be analysed at 
the local lab. Safety labs will be analysed at screening visit and at week 4, 10 and 14 +/- 1 week. 
3. Speckle Tracking Echocardiography and traditional echocardiography should be done at screening visit +/- 1 
month.  
 
 

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Table 5: Schedule of assessments – continued treatment Year 1 and 2 
Study period 
Continued treatment Year 1 and 2 
Week 
0 
4 
8 
12 
16 
20 
24 
28 
321 
Clinic visit 
92 
103 
11 
12 
13 
14 
15 
16 
17 
Vital signs 
 
 
X 
 
X 
 
X 
 
X 
Physical exam 
 
 
X 
 
X 
 
X 
 
X 
Concomitant med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma oxalate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Faeces 
 
 
X 
 
X 
 
X 
 
X 
Safety Labs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test5 
X 
 
 
 
 
 
X 
 
 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Speckle Tracking 
Echocardiography 
(X)6 
 
 
 
 
 
X7 
 
 
1. Treatment will continue until the patient is transplanted. The maximal length of the continued treatment period 
will be 36 months.  Visit intervals and examinations/samplings will be kept the same throughout the year 1 and 2 
of the continued treatment period.  
2 Visit 9 may coincide with visit 8 for patients continuing on treatment immediately after week 14 visit.  
3. Visit 10 will be scheduled 28 days (+/- 3 days) after first day of continued treatment after study week 14. 
4. Safety labs include: haematology analysis, clinical chemistry analysis and urinalysis and will be analysed at 
the local lab.  
5. Pregnancy test will be repeated every 6 months during the continued treatment period. 
6. For patients who did not have a Speckle Tracking/Traditional Echocardiography performed at screening, an 
effort will be made to perform this examination before start of continued treatment.  
7. Speckle Tracking/Traditional Echocardiography will be repeated every 6th month during the continued 
treatment period in weeks 0, 24, 48, 72 and 104. 
 
 
 
 
 
 

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Table 6 Schedule of assessments – continued treatment Year 3 
 
 
1. Safety labs include: haematology analysis, clinical chemistry analysis and urinalysis and will be analysed at 
the local lab. 
 
 

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6.2.1 Screening 
Patient Information must be given and the Informed Consent form 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 Informed 
Consent on a Screening and Inclusion log.  
The inclusion and exclusion criteria should be reviewed. Demographics and baseline 
data will be collected. These include: 
• Birthdate, height, weight. 
• Physical examination and Vital Signs. 
• PH medical history (including diagnosis, historical levels of urinary oxalate, renal 
function). 
• Other medical history, including concurrent illnesses and symptoms. 
• Concomitant medication. 
The following samples should be taken and sent for analysis: 
• Haematology analyses, clinical chemistry analyses and pregnancy test. 
• Urine sample for urinalysis, if possible.  
The patient should be on a stable dialysis regimen individualised to remove adequate 
oxalate to minimise the risk for systemic oxalosis for at least two weeks prior to 
baseline (two weeks before visit week 2). The regimen could be either HD or PD or a 
combination of HD and PD. The PD regimen (number of days/week, hours per 
treatment, volume of dialysis buffer) and HD regimen (number of days/week; hours per 
treatment; blood and dialysate flow rates; and HD membrane) will be maintained 
unchanged for the duration of the study. This will be monitored and recorded by 
measuring volume of spent dialysate from HD and PD and quantifying dialysis dose of 
each HD session in terms of Kt/V measurement using an online clearance monitor. 
Speckle Tracking Echocardiography and traditional echocardiography will be 
performed, if possible, at screening visit (+/- 1 month) or before start of continued 
treatment period (at visit week 14). Speckle Tracking Echocardiography will then be 
repeated at week 24 in the continued treatment period and thereafter every 6 months 
until end of treatment, if possible.  
The patient (and parents when applicable) will be instructed how to collect faeces 
samples, and dates for collection will be scheduled. See section 6.3 for further 
information on collections at patient´s home. For the course of the study, the patient 
should be instructed to maintain their normal diet and fluid intake as prescribed under 
their standard clinical care. The patient will be asked to avoid taking ascorbic acid 
preparations or multivitamin preparations during the study period. The patient will be 
scheduled for a week 2 visit. 
6.2.2 Baseline 
During baseline plasma oxalate sampling will be done at week 2 and 4. The blood 
sample will be taken after two consecutive days of dialysis on the preceding days, but 
prior to the dialysis session on the day of sampling. The blood sample will be processed 
at the clinical site and the acidified plasma will be shipped frozen to the central 

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laboratory (Academical Medical Center, Amsterdam, The Netherlands) for 
determination of oxalate using the Isotope dilution Gas Chromatography with mass 
selective detection (GC-MSD). Plasma oxalate will also be determined using the Ion 
Chromatography method at Bonn University Clinical laboratory, Germany. 
Safety labs and faecal testing for O. formigenes will be performed in week 4.  
The faeces sample will be collected either at patient´s home or at the clinic and shipped 
for analysis at Institut für Mikroökologie, Herborn, Germany. 
Any changes in concomitant medication will be recorded in the CRF at visit week 2 and 
4. At week 4 each patient’s eligibility will be reviewed to assure that no exclusionary 
conditions have developed since the screening visit. The result from the week 2 plasma 
oxalate sample (total plasma oxalate) will be reviewed for patient eligibility at this 
point.  
For patients who fail any of the inclusion or exclusion criteria, applicable parts of the 
CRF should be completed and they should be recorded as screening failures in the 
Screening and Inclusion log.  
After verification of the inclusion and exclusion criteria, the patient will be included in 
the study to receive study treatment.  
At the clinical visit week 4 the patient and/or the parents will be instructed about the 
administration procedures for the study drug. See section 8.1 regarding dose 
administration. The patient will be scheduled for clinic visits at week 6, 8, 10, 12 and 
week 14.  
6.2.3 Treatment period – the first 6-week treatment period (study week 5-10) 
During the initial 6 weeks treatment period, the patient will be followed by clinic visits 
at week 6, 8 and 10, according to Table 4: Schedule of assessments – the first 14 weeks 
of the study.  
At the clinic visits, a blood sample for plasma oxalate will be taken prior to the dialysis 
session.  
At week 10, faecal sample will be taken as well as safety labs.  
At each clinic visit the patient will be assessed for the presence or absence of Adverse 
Events and changes in concomitant medications.  
The patient will receive shipments of study drug bi-weekly at week 4, 6 and 8. 
Remaining study drug will be returned to the clinic or site pharmacy at clinical visits 
weeks 6, 8, 10 and 12.  
6.2.4 Post treatment period – 4 weeks without study drug (study week 11-14) 
During the post-treatment period study visits will take place at week 12 and 14. A blood 
sample will be taken for determination of plasma oxalate prior to the dialysis session in 
week 12 and 14. 
At week 14 faecal sample will be taken as well as safety labs.  
At each clinic visit the patient will be assessed for the presence or absence of Adverse 
Events and changes in concomitant medications. At the clinical visit week 14 a physical 
examination including vital signs will be performed. 

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Adverse Drug Reactions (i.e. AEs that are possibly or probably related to study 
treatment, see section 11.1), which are unresolved at the time of week 14 clinic visit, 
should be followed until the event has resolved or, if persistent, has been assessed as 
“chronic” or “stable” for patients not participating in the continued treatment period. 
6.2.5 Continued treatment period 
Addendum to the ICF needs to be signed for patients who agree to continue on 
treatment with study drug after the week 14 visit. During the first 24 months of the 
continued treatment period the patient will be followed by clinic visits every 4th week 
and during the last 12 months every third or fourth month, please see Table 5: Schedule 
of assessments – continued treatment Year 1 and 2 and Table 6 : Continued treatment 
Year 3. Patients who are already treated in year 3 of continued treatment at the time of 
implementation of this amendment will continue on the previous monthly visit schedule 
for year 3.  
At the clinic visits, blood samples will be taken, prior to the dialysis session, for plasma 
oxalate as well as for safety labs. Pregnancy test will be taken at continued treatment 
week 0 (clinic visit 9) and repeated every 6 months during the continued treatment 
period, for women of childbearing potential.  
Faecal sample will be taken every 8th week for the first 24 months of the continued 
treatment period and thereafter every 12th or 16th week.  
At each clinic visit the patient will be assessed for the presence or absence of Adverse 
Events and changes in concomitant medications.  
The patient will receive a shipment of study drug bi-weekly throughout the treatment 
period. Remaining study drug/empty vials 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 patient.  
Speckle Tracking Echocardiography and traditional echocardiography will be done. If 
the examination could not be done at screening, an effort will be made to perform the 
examination before start of continued treatment period (at week 0 of the continued 
treatment, clinic visit 9). The examination will then be repeated at week 24 in the 
continued treatment period and thereafter every 6 months until end of treatment.  
6.3 Specimen collection at patient’s homes  
The collections of faeces will be performed by the patients either in their home 
environment or at the clinic, and should be performed according to Table 4: Schedule of 
assessments – the first 14 weeks of the study, Table 5: Schedule of assessments – 
continued treatment Year 1 and 2 and  Table 6: Schedule of assessments – continued 
treatment Year 3. The sponsor will provide collection kits and a Patient Handbook 
describing the collection procedures. The delivery of collection kits to patients´ homes 
and pick-up of collections, if applicable, will be done by a courier. 
6.4 Diet 
For the course of the study, the patients 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 significant changes in their diet during the study specially related to high 
oxalate foods and fluid intake. 

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The patients will be asked to refrain from ascorbic acid preparations or multivitamin 
preparations during the study. Vitamins given as standard of care for patients on 
dialysis are allowed during the study.  
7 SELECTION AND WITHDRAWAL OF PATIENTS 
7.1 Patient inclusion criteria 
1. Signed informed consent (as applicable for the age of the patient). An appendix to 
the informed consent form will be signed by patients continuing on treatment after 
week 14. 
2. Male or female patients≥ 2 years of age. Patients have to be able to swallow size 4 
capsules twice daily, or use a gastric tube that allows for administration of size 4 
capsules. 
3. A diagnosis of PH (as determined by standard diagnostic methods). 
4. Patient should be on a stable dialysis regimen for at least two weeks before baseline.  
 
5. Plasma oxalate ≥40 micromole/L prior to the dialysis session.  
 
6. Patients receiving vitamin B6 must be receiving a stable dose for at least 3 months 
prior to screening and must remain on the stable dose during the study. Patients not 
receiving vitamin B6 at study entry must be willing to refrain from initiating vitamin 
B6 during study participation. 
 
7.2 Patient exclusion criteria 
7. Inability to swallow size 4 capsules twice daily, or using a gastric tube not suited for 
administration of size 4 capsules via the tube. 
8. Ongoing treatment with immunosuppressive medication. 
9. 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. 
10. Use of antibiotics to which O. formigenes is sensitive (see section 8.2.2), including 
current antibiotic use, or antibiotics use within 14 days of initiating study 
medication. 
11. Current treatment with a separate ascorbic acid preparation. Standard of care 
vitamin supplement for patients on dialysis are allowed.   
12. Pregnancy. 
13. Women of childbearing potential who are not using adequate contraceptive 
precautions.  Sexually active females, unless surgically sterile or at least 2 years post-
menopausal, must be using a highly effective contraception (including oral, 
transdermal, injectable, or implanted contraceptives, IUD, abstinence, use of a 
condom by the sexual partner or sterile sexual partner) for 30 days prior to the first 
dose of OC5 and must agree to continue using such precautions during the clinical 
study.   

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14. Presence of a medical condition that the Principal Investigator considers likely to 
make the patient susceptible to adverse effect of study treatment or unable to follow 
study procedures. 
15. Participation in any study of an investigational product, biologic, device, or other 
agent within 30 days prior to the first dose of OC5 or not willing to forego other 
forms of investigational treatment during this study. 
7.3 Patient withdrawal criteria 
If a patient fails to return for a scheduled study visit the investigator will make a 
reasonable effort to contact the patient and determine why the patient failed to return 
and to schedule a new study visit.  Any information obtained during this contact will be 
documented in the study records.   
A study patient will be discontinued from participation in the study if: 
• Any clinical 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 patient. 
• OxThera or the Principal Investigator in consultation with OxThera may 
discontinue the patient at any time for medical and/or administrative 
reasons. 
• The patient withdraws consent from participating in the study at any time. 
• The patient undergoes a transplantation procedure. 
• There are major protocol violations. 
Any patient who withdraws prematurely from the first 14 weeks of the study will be 
asked to complete all study assessments described for the week 14 clinical visit. For 
patients who withdraw during the continuation phase of the study, the last data 
collected will be that from the last performed study visit. 
For any patient who has withdrawn, the date of withdrawal from the study and the 
reason for withdrawal will be recorded in the source data and CRF. Adverse Drug 
Reactions (i.e. AEs that are possibly or probably related to study treatment, see section 
11.2), which are unresolved at the time of withdrawal, should be followed until the 
event has resolved or, if persistent, has been assessed as “chronic” or “stable”. 
Withdrawn patients should not be re-entered into the study. Additional patients, if 
available, may be enrolled at the discretion of the Sponsor. 
8 TREATMENT OF PATIENTS 
8.1 Description of study treatment 
The study drug consists of OC5 as the active treatment. The study drug is supplied as 
enteric-coated capsules. One capsule shall be administered orally with water twice daily 
with breakfast and dinner. For patients using a gastric tube the capsules may be 
administered through the tube. The study product is described in more detail in section 
9.  

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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. Patients 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.  
8.2.1 Concomitant treatment with vitamin B6 
Patients receiving vitamin B6 (pyridoxine) prior to study entry must be on a stable dose 
for at least 3 months prior to the screening visit. Patients who are not receiving vitamin 
B6 at study entry will not be allowed to initiate vitamin B6 during study participation. 
Patients 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 
Patients are not allowed to receive any other investigational therapies during study 
participation. 
Other prohibited medications are: 
- 
Ascorbic acid preparations: Ascorbic acid preparations must not be used during 
the study period. Standard of care vitamin supplements for patients on dialysis 
are allowed.    
- 
Multiple dosing antibiotics: Patients that require chronic antibiotics, or more 
than two courses of acute antibiotics, to which O. formigenes is sensitive will 
discontinue study drug and be followed for safety. If a short-term antibiotics 
therapy is indicated to treat acute bacterial infections, patients should receive 
standard of care.  
o O. formigenes has shown resistance to ceftizoxime, imipenem, ampicillin, 
amoxicillin and penicillin. These are the preferred antibiotics for standard 
of care.  
o O. formigenes has shown sensitivity to chloramphenicol, doxycycline, 
erythromycin, and tetracycline. 
- 
Immune suppressive therapy  
8.3 Treatment compliance 
Patients will be provided with a study drug diary to record doses taken/missed. 
Compliance to study treatment will be questioned at each visit to the clinic. Any missed 
doses or doses lost during handling will be registered. 
Unused medication will be returned to the clinic or site pharmacy at clinical visits weeks 
6, 8, 10 and 12 during the first 14 weeks of the study. The unused medication will be 
accounted for an overall check of compliance. 
For the continued treatment period, study drug 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 patient.   

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9 STUDY DRUG MATERIALS AND MANAGEMENT 
9.1 Study drug 
OC5 is the active treatment and is supplied as enteric-coated, size 4, gelatine capsules. 
One capsule contains NLT 1E+09 CFU. Details on the product are described in Table 7 
below. 
 
Table 7: Details of the study drug in the OC5-OL-01 study 
Parameter 
High Dose 
Active Substance 
Lyophilised O. formigenes, strain HC-1 
Name 
Oxabact® (OC5) 
Route of Administration 
Oral 
Dose form 
Enteric-coated capsule 
Viable cell count  
NLT 1E+09 CFU/dose, NMT 5E+10 CFU/dose  
Excipients 
Oligofructose, Maltodextrin, Alginate, Sucrose, 
Microcrystalline cellulose 
 
9.2 Study drug packaging and labelling 
Capsules will be filled into sealed aluminium tubes. A transition to tubes containing 18 
capsules rather than 14 capsules was done during 2019, to include some overage 
medication in each tube. A desiccant will be present in the lid of the tube. 
The label, including patient 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 each country´s regulatory requirement. 
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 patients. Study medication should be stored refrigerated (2°C to 8°C) at the 
patients’ 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 patients and will inform patients that study capsules should be stored 
refrigerated (2°C to 8°C) at their homes in securely sealed tubes. Patients will be 
supplied with sufficient capsules for two weeks treatment, every second week. 

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Unused study medication and empty vials will be returned to the clinic or site pharmacy 
at clinical visits weeks 6, 8, 10 and 12 for the first 14 weeks. For the continued 
treatment period, remaining unused study drug 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 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 sponsor. 
Investigational products deliberately and/or accidentally destroyed in transit or at a 
study site should be accounted for and documented.  
10 ASSESSMENT OF EFFICACY 
The main efficacy parameter to be assessed is: 
• Change in total plasma oxalate level during OC5 treatment, compared with an 
average of the baseline values. 
 
Secondary efficacy parameters to be assessed are: 
• To evaluate the efficacy of OC5 to reduce free plasma oxalate levels during OC5 
treatment in patients with Primary Hyperoxaluria (PH) who are on dialysis. 
• Change in number of O. formigenes in faeces during OC5 treatment. 
• Change in plasma oxalate values from week 10 to week 14, following the 4-week 
off-treatment period. 
• To evaluate results from Speckle Tracking Echocardiography and traditional 
echocardiography for patients where this examination could be performed. 
 
10.1 Plasma oxalate 
Samples for plasma oxalate will be collected during clinical visits, as specified in Table 4: 
Schedule of assessments – the first 14 weeks of the study, Table 5: Schedule of 
assessments – continued treatment Year 1 and 2 and Table 6: Schedule of assessments 
Year 3. These samples have to be taken after two consecutive days of patient’s standard 
dialysis regimen, but prior to the dialysis session on the day of sampling. 
Samples for plasma oxalate will be processed at the clinical site and analysed for total 
plasma oxalate concentration at Academic Medical Center, Amsterdam, the Netherlands 
using Isotope dilution Gas Chromatography with mass selective detection (GC-MSD). 
Samples will also be analysed for free plasma oxalate at the University Clinical 
laboratory in Bonn using Ion Chromatography (IC). Each site will be provided with kits 
and supplies for collection, processing and shipping of blood samples for determination 
of plasma oxalate. Complete instructions for the collection, processing, storage and 
shipping of sample will be provided in the site manual. Available local lab results for free 
plasma oxalate performed as standard of care during the study, but before the effective 
date for Amendment VII (which introduced this analysis method in the protocol) will be 
captured retrospectively and included in the statistical analysis.  
 

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10.2 Quantification of O. formigenes 
The possibility to monitor the natural occurrence of O. formigenes bacteria and the 
presence of the O. formigenes bacteria during and after treatment with OC5 is an 
important tool for control of the pharmacodynamics of the drug. A real-time 
quantitative PCR assay will be used that permits determination of the levels of O. 
formigenes and its change over time in faecal samples.  
Faecal samples will be collected either at patients’ home or at the clinic and shipped to 
central laboratory MVZ Institut für Mikroökologie GmbH, Auf den Lüppen 8, 35745 
Herborn, Germany. 
10.3 Speckle Tracking Echocardiography and Traditional 
Echocardiography 
Speckle Tracking Echocardiography is currently evaluated as a method to detect and 
quantify oxalate deposits in the heart muscle.13 Speckle Tracking Echocardiography and 
traditional echocardiography will be performed at screening (alternatively before start 
of continued treatment) and repeated every 6 months during the continued treatment 
period, if possible. The examination will be performed locally using specific equipment. 
Images will be interpreted by a central reader who is blinded to plasma oxalate and 
examination date. 
Speckle Tracking Echocardiography 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 (Ejection Fraction, End Diastolic Volume, e/é, e/a, Left 
Ventricular End Diastolic Dimension, Fractional Shortening, Tricuspid Regurgitation by 
Doppler as an indicator of RV/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 LV and RV function to 
determine which assessment of cardiac function is more sensitive in these patients. 
Speckle Tracking Echocardiography examinations performed during the study, but 
before this amendment´s effective date will be re-evaluated to retrospectively capture 
the above-mentioned parameters to be included in the statistical analysis.  
11 ASSESSMENT OF SAFETY 
The safety parameters to be assessed are: 
• Adverse Events 
• Laboratory safety measurements  
 
 

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11.1 Definition of Adverse Events 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study patient 
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 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 and results in hospitalisation, 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 patient’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. 
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 patient’s death 
• is life-threatening* 
• requires inpatient hospitalisation or prolongation of existing hospitalisation** 
• persistent or significant disability/incapacity; or 

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• congenital anomaly/birth defect 
• corresponds to other important medical event as determined by the Investigator. 
*   Life threatening means that the patient 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 patient’s death. Life threatening does not 
mean that had an AE occurred in a more severe form it might have caused death. 
** Hospitalisation 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 patient 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 11.4). 
11.2 Relationship to study drug 
The following relationships to study drug will be used in the study.  Events classified as 
possible, probable, or definitely will be considered related to study drug. 
Not related:  
The event does not follow a plausible chronological sequence relative to trial medication 
administration and can be clearly assigned to other factors, such as patient’s clinical 
condition, therapeutic procedures or administration of concomitant medications. 
Possible:  
There is sufficient information to accept the possibility of a causal relationship, although 
the connection is uncertain or doubtful, i.e. causal relationship is not impossible and not 
unlikely.  The event follows a plausible chronological sequence relative to trial 
medication administration and/or presents the usual response to the drug tested.  The 
event might also be caused by other factors, such as the patient’s clinical condition, 
therapeutic procedures or administration of concomitant medications. 
Probable:  
There are good reasons and sufficient documentation to assume a causal relationship in 
the sense of plausible, conceivable, likely, but not necessarily highly probable. The event 
follows a plausible chronological sequence relative to trial medication administration 
and/or presents an unexpected response to the trial drug and cannot reasonably be 
explained by other factors, such as the patient´s clinical condition, therapeutic 
procedures or administration of concomitant medications. 
Definitely:  
When the event cannot be attributed to the patient’s underlying medical condition or 
other concomitant therapy and there is compelling temporal relationship between the 
onset of the event and the study investigational product administration that leads the PI 
to believe there is evidence of a reasonable causal relationship. 

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11.3 Recording Adverse Events 
Each patient will be questioned about AEs at each clinic visit/ following initiation of 
treatment. The question asked will be "Since your last clinic 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 patients or by lab results. 
The investigator is to record in the CRFs all directly observed AEs, all AEs as a response 
of the open question and all AEs spontaneously reported by the patient 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* (mild, moderate or severe), 
• Seriousness (serious or not serious, according to definition), 
• Causal relationship, (definitely, possible, probable, unrelated)  
• Action taken, (none, treatment required, patient 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. 
* For each reported AE, the intensity will be recorded. The following definitions of 
intensity are to be used: 
o Mild: A mild AE means awareness of symptoms or signs, but easily tolerated 
(acceptable).  
o Moderate: A moderate AE means enough discomfort to interfere with usual 
activity (disturbing). 
o Severe: A severe AE means incapacity to work or to do usual activity 
(unacceptable) 
If the intensity 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 CRF. 
11.4 Reporting Adverse Events 
Adverse Event reporting on each patient shall start at the initiation of study treatment. 
The reporting shall continue during the course of the study. Spontaneously reported 
events by study patients in between planned visits shall also be reported. Adverse Drug 
Reactions, which are unresolved at the time of the last follow-up visit should be 
followed until the event has resolved or, if persistent, has been assessed as “chronic” or 
“stable”. AEs should be reported for all patients, independent of treatment assignment. 
NON-SERIOUS AEs are to be reported in the CRF. 
SAEs are to be reported by the investigator to ProductLife Department via the form in the 
eCRF or via fax (+44 1223 413689) or email (safety@productlife-group.com).  

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In case of any question related to SAE reporting please contact Drug Safety Physician/ 
Medical Monitor, see contact information in Table 1. The initial SAE form (provided in 
the eCRF and in the Investigational Site File (ISF)) should be completed within 24 hours 
of awareness of the event. All SAEs must be reported whether or not considered drug 
related. SAEs should also be reported in the CRF. 
Completed Serious Adverse Event Reports should be submitted to ProductLife 
Pharmacovigilance Department within 24 hours of awareness by eCRF, fax (+44(0) 1223 
413 689) or email (safety@productlife-group.com). 
After receipt of the initial report, ProductLife Pharmacovigilance Department will 
forward the information to OxThera. Timelines for reporting and forwarding 
information are detailed in the Safety Management Plan. 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 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.   
An Unexpected Adverse Reaction is any adverse reaction, the specificity or severity of 
which 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. 
The investigator is responsible for ensuring that there are procedures and expertise 
available to handle emergencies during the study.  
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), see Table 3. OC5 has been 
evaluated in one completed double-blind placebo-controlled multicentre international 
phase II study, the current ongoing phase II open-label study, and two ongoing phase III 
trials, 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 all the completed studies indicate that patients may 
experience headache and gastrointestinal symptoms including abdominal pain, 

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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 Oxabact® and placebo. 
As a safety precaution, children were not treated with OC5 in the OC5-OL-01 study until 
the 4-week safety data from at least two adult patients in the OC5-DB-01 study had been 
reviewed. 
11.5.1.1 Safety data for OC5-DB-01 study 
28 patients were randomised in the OC5-DB-01 trial; 14 patients received OC5 and 14 
patients received placebo. The first patient was enrolled in December 2013 and the last 
patient last visit (LPLV) was in January 2015. 
There were 67 adverse events (AEs) and three serious adverse events (SAEs) reported 
throughout the OC5-DB-01 study. These are summarised in Table 8 and Table 9 below. 
 
Table 8: Summary of all adverse events in OC5-DB-01 (safety analysis set). 
 
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 patients; m: Number of mentions 
Percentage is based on number of patients in safety analysis set 
 
Three patients (all in the OC5 group) experienced SAEs. No SAE was judged to be related 
to the treatment and none required a change in dose. Brief summaries of the SAEs are 
presented as follows: 
• 
Patient SCR01-0009: a 16-year-old male experienced radius fracture approximately 
1 month after initiation of OC5 treatment.  
• 
Patient SCR02-0001: a 13-year-old female experienced pyelonephritis 
approximately 7 weeks after initiation of OC5 treatment. Her condition was judged 
to be severe and unrelated to the study treatment.  

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• 
Patient SCR03-0005: an 18-year-old male experienced renal colic approximately 
6 weeks after initiation of OC5 treatment. His condition was judged to be severe and 
unrelated to study treatment.  
 
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 patients; m: Number of mentions 
Adverse events are coded according to MedDRA version 16.1 
Percentage is based on number of patients in safety analysis set 
 
 
Ten patients (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 patients 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 patients in the OC5 group than in the Placebo group (four 
patients [29%] versus no patients [0%]), only one occurrence was considered related to 
the treatment (Patient SCR01-0002; kidney pains, moderate, possibly related). 
Two AEs were judged to be definitely related to treatment. Patient SCR01-0001 (OC5) 
experienced a case of mild rumbling stomach, which began the day that treatment 
commenced and resolved the day after treatment ended. Patient SCR07-0004 (Placebo) 
experienced a case of mild diarrhoea the day after treatment started. 

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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. 
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. 
11.5.1.2 
Safety data for the ongoing studies OC5-OL-01, OC5-DB-02 and OC5-
OL-02  
The current OC5-OL-01 study started in May 2014 and is ongoing in Germany. Fourteen 
subjects were screened and 12 subjects have been enrolled in the study and received 
study drug. This study includes late-stage patients with ESRD who are on dialysis. Most 
of these patients are on a waiting list for transplantation. Eight subjects continued into 
the continued treatment phase of the study, and one subject currently remains in the 
study (as of September 2019). There have been no severe nor serious related AEs for 
Oxabact in this ongoing study. 
In the ongoing, double-blind OC5-DB-02 study in patients with retained but reduced 
kidney function (eGFR <90ml/hr/1.73m2), 16 patients have been randomised. There 
have been 8 SAEs reported to-date; none of them was considered related to study drug. 
There have been no reported SAEs in the ongoing open-label OC5-OL-02 study 
(currently 4 enrolled patients). 
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. 
11.5.2 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. In the completed clinical 
studies, no patient experienced any infection due to O. formigenes.  
Any patient who develops signs and symptoms of bacteremia requiring hospitalisation 
should be evaluated to identify the source of infection (e.g., lung, GI tract, meningeal, 
etc.). 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 
patient. 
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 

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responding to erythromycin or tetracycline the study medication should be stopped 
until further evaluation. 
11.5.3 Elevated levels of plasma formate 
Since Oxalobacter formigenes converts oxalate to formate, there may be the possibility of 
elevated plasma formate levels following administration of high doses of OC5. 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. 
Previous studies with Oxabact® (including OC2, OC3 and OC5) in over 100 patients with 
doses ranging from NLT 107 to NLT 109 CFU have not indicated any 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 
patient 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).  
Formate accumulation in plasma is the main reason for acidosis in early, uncomplicated 
stages of metabolic acidosis.14 Metabolic acidosis is characterised 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 or blood pH will serve as an indication 
of elevated levels of formate. The OC5-OL-01 study will investigate these early signs of 
elevated plasma formate as part of routine safety labs. Low levels of serum bicarbonate 
or blood pH 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: Complete Blood Count (CBC) with differential and platelet 
count.  
• Chemistry:  Blood Urea Nitrogen (BUN), creatinine, electrolytes (Na+, K+, 
Mg++, Ca++, HCO3-, Cl), glucose, pH, albumin, alkaline phosphatase, ALT, 
AST, total bilirubin, and total protein.  
• Random Urine (Urinalysis):  protein, glucose, pH. 
Laboratory parameters from haematology, chemistry and urinalysis will be assessed at 
the local laboratory at each clinic. Laboratory safety tests will be performed as specified 
in Table 4: Schedule of assessments – the first 14 weeks of the study, Table 5: Schedule 
of assessments – continued treatment Year 1 and 2 and Table 6: Schedule of 
assessments – continued treatment Year 3. 

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12 STATISTICS 
12.1 Statistical methods 
Efficacy: The primary endpoint, change in total plasma oxalate from baseline, will be 
evaluated over time for each patient. Evidence for efficacy will be provided as the 
combined evaluation of individual case studies. Plasma oxalate levels will be measured 
on a monthly basis throughout the first 24 months of the continued treatment period 
and once every 3-4 months during the last 12 months of the continued treatment period. 
All secondary endpoints will be analysed using the same methodology.  
For the primary endpoint the change in total plasma oxalate levels will be based on the 
average from two baseline measurements (week 2 and week 4) and one measurement 
every 4th week throughout the first 24 months of the continued treatment period and 
every 3-4 months during the last 12 months of the continued treatment period.  
The change in plasma oxalate during 4 weeks follow-up period after the end of the 6 
weeks treatment period with OC5, will be based on one measurement at week 10 and 
one measurement at week 14. The last observation will be carried forward in case of 
missing values at week 14 and/or week 10. 
Two interim analyses will be performed: The first analysis will be based on patients who 
complete the first year of continued treatment.  The second interim analysis will be 
based on all study data obtained up to 24 months. Both interim analyses will evaluate all 
captured efficacy and safety parameters. 
The individual changes in plasma oxalate per week will also be calculated as an average 
slope using regression of plasma oxalate by week. 
The study involves a small number of patients and natural history data on changes in 
total and free plasma oxalate for this population is limited.  Response to treatment is 
likely to vary depending on the baseline plasma oxalate level, individual hepatic oxalate 
production and age of each patient. Accordingly, the sample size is not based on 
assumptions of efficacy outcome and statistical power, and the definition of analysis 
populations is not applicable. Any inferences from the data will be based on clinical 
relevance rather than statistical significance. 
Safety: The safety will be summarised using descriptive statistics based on frequency, 
seriousness and severity of treatment emergent AEs. Clinically relevant changes in 
safety laboratory parameters will also be summarised. 
All statistical analyses will be further defined in a Statistical Analysis Plan.  

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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 patient 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 CRFs 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 every patient, the medical records should include the minimum following 
information: 
• patient 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 CRF, 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. 
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 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 

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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. 
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 patients 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 such as the reporting of SAEs and the final study report. 
15.3 Written informed consent 
It is the responsibility of the investigator to give each patient, 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 patients 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 patient is 
otherwise entitled. The patients should be informed that the results will be stored and 
analysed digitally, maintaining confidentiality in accordance with local data protection 
laws. 
Furthermore, it is the responsibility of the investigator to obtain signed informed 
consent from all patients 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 patient and/or parental consenting should depend on the age 
of the patient. The investigator or his/her designated representative, who gave the 
verbal and written information about the study to the patient, must also sign the 
informed consent form. A copy of the written patient information must be handed to 
each patient, to bring home. The investigator will confirm the receipt of informed 
consent from each patient by a recording in the CRF. The signed Informed Consent 
forms should be filed by the Investigator in the Investigator File for possible future 
audits and inspections.  

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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 each country’s regulatory 
requirements. As with the IEC, clinical trial authorisation 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 SUSAR reports and 
annual safety updates or as required by local country regulations, and be notified of the 
end of the trial. 
16 DATA HANDLING AND RECORDKEEPING 
16.1 Case report forms 
A Case Report Form (CRF) is required and should be completed for each included 
patient. The CRF 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 
CRFs. 
Data validation will be performed after data have been entered, signed and monitored 
by computerised logical checks. Any discrepancies found in the data will generate 
queries. The queries will be sent to the site personnel and the responsible site monitor 
for further action. 
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 patient’s privacy is maintained. On the CRF or 
other documents submitted to OxThera, patients will be identified by a patient 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 patient s’ records and source document for 
the purposes of monitoring, auditing, or inspection by OxThera, authorised 
representatives of OxThera, Regulatory Authorities and IECs. 

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As part of the required content of the informed consent, patients 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 authorisation, it is the 
Investigator’s responsibility to obtain such permission from the patient in writing 
before the patient is entered into the study. 
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 and by a separate 
Indemnification Agreement between the sponsor and the Institution if applicable. 
OxThera has civil liability insurance, which covers this study in all participating 
countries. 
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 CTA. They can be 
summarised 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 patients have 
completed the study and the study has been analysed. If there is a publication, the 
Investigator that has the highest number of treated patients will be the lead author. The 
investigator may not publish the results of their cohort of patients 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. 
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 patients. All changes to the final study protocol must be documented in a 
written protocol amendment. 
 

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20 REFERENCES 
1. Cochat P. and Rumsby G. Primary Hyperoxaluria, N Engl J Med 369, 649-658, 
2013. 
2. Hoppe B. An update on primary hyperoxaluria. Nature Reviews Nephrology, 8, 
467-475, 2012. 
3. Zhao F et al., Predictors of Incident ESRD among Patients with Primary 
Hyperoxaluria Presenting Prior to Kidney Failure.  Clin J Am Soc Nephrol. 2016, 
Jan 7; (11(1):119-26. 
4. Hoppe B, Beck B and Milliner D. The Primary Hyperoxalurias. Kidney Int. 75, 
1264-71, 2009. 
5. Hoppe B. et al Oxalate elimination via hemodialysis or peritoneal dialysis in 
children with chronic renal failure. Pediatr Nephrol, 10, 488-492, 1996. 
6. Leumann E and Hoppe B. The Primary hyperoxalurias, J. Am Soc Nephrol. 12, 
1986-1993, 2001. 
7. Stewart CS, Duncan SH and Cave DR. Oxalobacter formigenes and its role in 
oxalate metabolism in human gut. FEMS Microbiol. Lett. 230, 1-7, 2004. 
8. Hatch M and Freel RW. Intestinal transport of an obdurate anion: oxalate. Urol. 
Res. 33, 1-16, 2005. 
9. 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 
10. Hoppe B. et al. Oxalobacter formigenes: a potential tool for the treatment of 
primary hyperoxaluria type 1. Kidney Intl., 70, 1305–1311, 2006. 
11. 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 Sep;58(3):453-5.  
12. 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;66:1056–1058, 2007. 
13. 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. 
14. Sejersted O. et al. Formate concentrations in plasma from patients poisoned with 
methanol. Acta Med Scand. 1983; 213(2):105-10. 
 
 
 
 

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21 APPENDICES 
Appendix 1: Study protocol approval by investigator