Conditions: Loiasis
Keywords: Cameroon Filaricidal Randomized Blinded Diethylcarbamazine Imatinib Loa loa
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
Background:

Many people who live in west or central Africa are at risk for infection from a very small worm called Loa loa. This infection is acquired through the bite of a fly. Baby worms called microfilariae live in the blood. The infection most commonly causes skin itching, mild temporary limb swelling, and sometimes a adult worm can be seen in the white of the eye of an infected individual. Very rarely, people with this infection can develop problems with the kidneys and heart as a result of the worm's effect on the immune system. Because the vast majority of people with the infection have minimal symptoms, people in Cameroon usually do not get treated. But infection with Loa loa can cause serious problems in people who are being treated for infections with other parasites (namely, river blindness and lymphatic filariasis). Researchers want to find out of a drug called imatinib can treat Loa loa infection so that patients with this infection can safely receive other drugs to cure river blindness and lymphatic filariasis. Researchers believe imatinib can be a safe drug to use on Loa loa, because in the lab this drug kills the worms slowly, whereas other drugs which can cause treatment reactions usually kill the worms very quickly.

Objective:

To test if imatinib can treat Loa loa infection by killing the worms slowly.

Eligibility:

People ages 18-65 with non-severe Loa loa infection who are otherwise healthy

Design:

Participants will be screened with a physical exam and blood and urine tests.

Participants will have a baseline visit. This will include a physical exam and blood and urine tests. It may include a stool sample. Participants will be randomly assigned to get 1 dose of either imatinib or a placebo.

Participants will return to the clinic every day for 1 week, then once a week for 3 weeks. Visits will include a physical exam and blood tests. They will have urine tests in the first week.

Participants will have follow-up visits 3, 6, and 12 months after taking the imatinib or placebo. These include a physical exam and blood tests. They may include urine and stool samples.

If participants develop side effects, they will be treated for them.

Detailed description:
With the discovery that people experiencing severe treatment reactions following mass drug administration (MDA) with ivermectin for onchocerciasis and lymphatic filariasis control were co-infected with Loa loa, there has been a need for new filaricidal drugs. Currently, Loa loa infection, considered relatively nonpathogenic, is not treated in endemic areas. However, because treatment for Loa loa can result in toxicity in people who are being concurrently treated for onchocerciasis and lymphatic filariasis, finding a new treatment for Loa loa has become a priority. Imatinib has recently been shown to be microfilaricidal in vitro at concentrations physiologically achievable after a single oral dose in humans. The current standard in loiasis treatment outside of endemic areas is to treat those with low microfilarial (MF) levels (less than approximately 8,000MF/mL) with diethylcarbamazine (DEC). However, at high MF concentrations (\>20,000 MF/mL) serious side effects including encephalopathy and death have occurred with administration of DEC or ivermectin, a widely distributed microfilaricide throughout Africa. In endemic areas, this risk is avoided by not treating loiasis altogether. The adverse reactions are believed to be due release of a large antigen load due to rapid killing of large numbers of MF. The rapidity of killing is believed to be the main driver of these reactions seen at high MF counts. The purpose of this study is to assess how imatinib acts as a slow microfilaricide at levels (\<2,500 MF/mL) that have been safely treated previously with DEC and ivermectin. We aim to perform a dose escalation study to identify the minimum single oral dose that will be effective as a slow microfiaricidal drug against Loa loa. If imatinib is found to be effective and have kinetics which favor slow microfilarial killing, then this can serve as the basis for a larger study in which patients with very high microfilarial loads would be treated, as this is the at risk population in current MDA campaigns. This is a double blind, randomized, pilot phase 2 dose-escalation trial. Subjects will receive a dose of imatinib at 200, 400 or 600 (n = 5 each). Symptoms and blood microfilarial concentration will be assessed at baseline, daily for the first 7 days, then weekly for the next 21 days, then at 3, 6, and 12 months. These will be compared against an untreated placebo-controlled group of 5 subjects who will have the same data collected at these respective days.

Arms:
arm 1: Subjects given vitamin placebo arm 2: Subjects given a single dose of imatinib 200mg PO arm 3: Subjects given a single dose of imatinib 400mg PO arm 4: Subjects given a single dose of imatinib 600mg PO

Interventions: intervention 1: Imatinib Mesylate intervention 2: Imatinib Mesylate intervention 3: Imatinib Mesylate intervention 4: Placebo
Intervention descriptions: intervention 1: A single dose of imatinib 200mg PO is given intervention 2: A single dose of imatinib 400mg PO is given intervention 3: A single dose of imatinib 600mg PO is given intervention 4: A single dose of placebo pill is given

Protocol document:
Prot_SAP_000.pdf: 
A double-blinded, randomized, placebo- 
controlled dose escalation study to examine 
the microfilaricidal kinetics and safety of 
imatinib for the treatment of Loa loa 
(A pilot study) 
NCT02644525 
NIAID Protocol Number: 16-I-N042 
Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
Centre de Recherche sur les Filarioses et autres Maladies Tropicales 
(CRFilMT) 
Principal Investigator (US): Elise M. O’Connell 
Principal Investigator (Cameroon): Joseph Kamgno 
Accountable Investigator: Thomas B. Nutman 
Version Number: 10.0 
November 18, 2019 
Page 1 of 34 


Imatinib in loiasis 
Version 10.0 
Page 2 of 34 
Study Staff Roster 
Principal Investigator/Study Coordinator: 
Elise O’Connell, MD, LPD/NIAID 
NIH/NIAID/LPD 
Bldg 4, Room B105 
Bethesda, MD 20892 
Tel. 301-761-5413 
Fax: 301-480-3757 
oconnellem@niaid.nih.gov 
Associate Investigators: 
Michael Fay, PhD, BRB/NIAID 
Thomas B. Nutman, MD, LPD/NIAID 
Collaborating Institutions: 
Centre de Recherche sur les Filarioses et Autres Maladies Tropicales 
(CRFilMT) 
FWA00023685 
Joseph Kamgno, MD, PHD 
Centre de Recherche sur les Filarioses et Autres Maladies Tropicales 
BP: 5797 
Yaoundé Cameroun 
Tél: 00237 22 20 24 42 
Fax: 00237 22 20 24 43 
kamgno@crfilmt.org 
Study Site: Mbalmayo, Cameroon 


Imatinib in loiasis 
Version 10.0 
Page 3 of 34 
The 
imag
e 
part 
with 
relat
ions
hip 
ID 
rId1
4 
was 
not 
foun
d in 
the 
file.
Table of Contents 
Study Staff Roster ................................................................................................. 2 
Table of Contents .................................................................................................. 3 
List of Abbreviations .............................................................................................. 5 
Protocol Summary ................................................................................................. 6 
Précis .................................................................................................................... 8 
1 
Background Information and Scientific Rationale ........................................... 9 
1.1 Background Information ..................................................................... 9 
1.2 Imatinib ............................................................................................ 10 
1.3 Rationale .......................................................................................... 10 
2 
Study Objectives .......................................................................................... 11 
2.1 Primary Objective: To determine the short-term microfilaricidal 
kinetics of imatinib against Loa loa. ................................................................. 11 
2.2 Secondary Objectives ...................................................................... 11 
2.3 Exploratory Objectives ..................................................................... 11 
3 
Study Design ................................................................................................ 11 
3.1 Description of the Study Design ....................................................... 11 
3.2 Primary Endpoint ............................................................................. 12 
3.3 Secondary Endpoints ....................................................................... 12 
3.4 Exploratory Endpoints ...................................................................... 12 
4 
Study Population .......................................................................................... 12 
4.1 Rationale for Subject Selection ........................................................ 12 
4.2 Recruitment Plan ............................................................................. 13 
4.3 Subject Inclusion Criteria ................................................................. 13 
4.4 Subject Exclusion Criteria ................................................................ 13 
4.5 Justification for Exclusion of Special Populations ............................ 14 
5 
Study Agent/Interventions ............................................................................ 14 
5.1 Disposition and Dispensation ........................................................... 14 
5.2 Formulation and Packaging ............................................................. 14 
5.3 Study Agent Storage and Stability ................................................... 15 
5.4 Preparation, Administration, and Dosage of Study Agent ................ 15 
5.5 Assessment of Subject Compliance with Study Agent .................... 15 
5.6 Concomitant Medications and Procedures ...................................... 15 
6 
Study Schedule ............................................................................................ 15 
6.1 Screening (Days −14 to −1) ............................................................. 15 
6.2 Baseline and Randomization (Day 0) .............................................. 16 
6.3 Study Phase (Days 1 to 28) ............................................................. 16 
6.4 Follow-up and Final Study Visits ...................................................... 17 
6.5 Early Termination Visit ..................................................................... 17 
6.6 Final disposition for participant ........................................................ 17 
7 
Study Procedures/Evaluations ..................................................................... 17 
7.1 Clinical Evaluations .......................................................................... 17 
7.2 Laboratory Evaluations .................................................................... 18 
7.2.1Clinical and Laboratory Evaluations and Specimen Collection 18 
7.2.2 Specimen Preparation, Handling and Shipping ...................... 18 
8 
Potential Risks and Benefits ......................................................................... 18 
8.1 Potential Risks ................................................................................. 18 


Imatinib in loiasis 
Version 10.0 
Page 4 of 34 
The image 
part with 
relationshi
p ID rId14 
was not 
found in 
the file.
8.1.1Imatinib .................................................................................... 18 
8.1.2Blood draws ............................................................................ 19 
8.1.3Microfilarial Death. ................................................................... 19 
8.2 Potential Benefits ............................................................................. 19 
9 
Research Use of Stored Human Samples, Specimens or Data ................... 19 
10 
Remuneration Plan for Subjects ............................................................... 20 
11 
Assessment of Safety ............................................................................... 20 
11.1 Toxicity Scale ................................................................................. 20 
11.2 Recording/Documentation ............................................................. 21 
11.3 Causality ........................................................................................ 21 
11.4 Reporting Procedures .................................................................... 22 
11.4.1 Expedited Reporting to the NIAID IRB .............................. 22 
11.4.2 Annual Reporting to the NIAID IRB ................................... 22 
11.4.3 Pregnancy ......................................................................... 22 
11.5 Type and Duration of Follow-up of Subjects after Adverse Events 22 
11.6 Halting Rules for the Protocol ........................................................ 23 
11.6.1 Reporting a Study Halt ...................................................... 23 
11.6.2 Resumption of a Halted Study .......................................... 23 
11.7 Discontinuation of Study ................................................................ 23 
11.8 Withdrawal Criteria for an Individual Subject ................................. 23 
11.9 Replacement of Withdrawn Subjects or Subjects who Discontinued 
11.10 Study Agent ................................................................................. 24 
11.11 Safety Oversight .......................................................................... 24 
12 
Site Monitoring Plan ................................................................................. 24 
13 
Statistical Considerations ......................................................................... 25 
13.1 Study Hypotheses .......................................................................... 25 
13.2 Sample Size Justification ............................................................... 25 
13.3 Final Analysis Plan ......................................................................... 25 
13.4 Planned Interim Analyses .............................................................. 27 
13.5 Safety Analysis .............................................................................. 27 
14 
Ethics/Protection of Human Subjects ....................................................... 28 
14.1 Informed Consent Process ............................................................ 28 
14.2 Subject Confidentiality ................................................................... 28 
15 
Data Handling and Record Keeping ......................................................... 28 
15.1 Data Capture and Management ..................................................... 28 
15.2 Record Retention ........................................................................... 29 
Scientific References .......................................................................................... 29 
Appendix A: ......................................................................................................... 32 
Schedule of Evaluations ...................................................................................... 32 
Appendix B: ......................................................................................................... 33 
Blood Volumes for Specimen Collection ............................................................. 33 
Appendix C .......................................................................................................... 34 
: Symptom/signs assessment ............................................................................. 34 


Imatinib in loiasis 
Version 10.0 
Page 5 of 34 
List of Abbreviations 
AE 
Adverse Event 
AI 
Associate Investigator 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
BRB 
Biostatistics Research Branch 
CFR 
Code of Federal Regulations 
Cmax 
Maximum concentration 
CML 
Chronic Myelogenous Leukemia 
CRF 
Case Report Form 
CRFilMT 
Centre de Recherche sur les Filarioses et Autres Maladies 
Tropicales 
CRIMSON 
Clinical Research Information Management System of the NIAID 
DALY 
Disability-Adjusted Life Year 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
FMPOS 
Faculty of Medicine, Pharmacy and Odontostomatology 
GCP 
Good Clinical Practice 
GXDn 
Day n of Group X 
IC50 
Concentration Producing 50% Inhibition 
ICER 
Mali International Center for Excellence in Research 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LF 
Lymphatic Filariasis 
LPD 
Laboratory of Parasitic Diseases 
MDA 
Mass Drug Administration 
MF 
Microfilaria 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PO 
Oral(ly) 
qPCR 
Quantitative Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SERF 
Safety Expedited Report Form 
UP 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 
USTTB 
University of Sciences, Techniques, and Technologies of Bamako 


Imatinib in loiasis 
Version 10.0 
Page 6 of 34 
Protocol Summary 
Full Title: 
A double-blinded, randomized, placebo-controlled 
dose escalation study to examine the microfilaricidal 
kinetics and safety of imatinib for the treatment of Loa 
loa (A pilot study) 
Short Title: 
Imatinib in loaiasis 
Clinical Phase: 
Phase II pilot study 
Conducted by: 
LPD/NIAID/NIH 
Principal Investigators: Elise M. O’Connell, MD (NIH) and Joseph Kamgno, 
MD, PhD (CRFilMT and FMBS/UYI) 
Accountable 
Investigator: 
Thomas B. Nutman, MD 
Sample Size: 
N=20 total (placebo controls n=5, 200mg n=5, 400mg 
n=5, 600mg n=5) 
Accrual Ceiling: 
200 
Study Population: 
Otherwise healthy volunteers infected with Loa loa 
between the ages 18-65 from Loa loa-endemic 
regions of Cameroon 
Accrual Period: 
2 years of enrollment. 
Study Design: 
This is a double-blinded, randomized, placebo- 
controlled multi-armed dose escalation study in which 
increasing imatinib doses will be given to different 
subjects (each not to receive more than 1 dose). 
Study Duration: 
24 months 
Start Date: September, 2019 
End Date: August, 2021 
Study Agent/ 
Intervention Description: Imatinib mesylate 200mg, 400mg, or 600mg, given 
one time orally 
Primary Objective: 
To model the short-term microfilaricidal kinetics of 
imatinib against Loa loa for use in designing follow-up 
studies. 
Secondary Objectives: 
To assess the safety of a single dose of imatinib in 
Loa loa infection 
Exploratory Objectives: To assess laboratory abnormalities associated with 
potential killing of Loa loa microfilariae; and to 


Imatinib in loiasis 
Version 10.0 
Page 7 of 34 
determine the efficacy of single-dose imatinib as a 
microfilaricide at 1-, 3-, 6-, and 12-month time points. 
Endpoints: 
Primary: 
Percent of baseline Loa loa microfilariae as determined by concentrated 
peripheral blood smear. Daily measurements will be taken the first week, 
followed by measurements at day 14 and day 21. 
Secondary: 
Tables of adverse events by treatment group including grades of AEs, as defined 
by CTCAE (Common Terminology Criteria for Adverse Events v5.0). 
Exploratory: 
Exploratory endpoints will include laboratory testing and complete blood count 
with white blood cell differential, as well as urine and stool assessment of 
coincident parasitic infections at multiple time points following imatinib used as a 
microfilaricide. 
Percent of baseline Loa loa microfilariae over time: 1, 3 months (and if needed 6 
and 12 months) 


Imatinib in loiasis 
Version 10.0 
Page 8 of 34 
Précis 
With the discovery that people experiencing severe treatment reactions following 
mass drug administration (MDA) with ivermectin for onchocerciasis and 
lymphatic filariasis control were co-infected with Loa loa, there has been a need 
for new filaricidal drugs. Currently, Loa loa infection, considered relatively non- 
pathogenic, is not treated in endemic areas. However, because treatment for Loa 
loa can result in toxicity in people who are being concurrently treated for 
onchocerciasis and lymphatic filariasis, finding a new treatment for Loa loa has 
become a priority. Imatinib has recently been shown to be microfilaricidal in vitro 
at concentrations physiologically achievable after a single oral dose in humans. 
The current standard in loiasis treatment outside of endemic areas is to treat 
those with low microfilarial (MF) levels (less than approximately 8,000MF/mL) 
with diethylcarbamazine (DEC). However, at high MF concentrations (>20,000 
MF/mL) serious side effects including encephalopathy and death have occurred 
with administration of DEC or ivermectin, a widely distributed microfilaricide 
throughout Africa. In endemic areas, this risk is avoided by not treating loiasis 
altogether. The adverse reactions are believed to be due release of a large 
antigen load due to rapid killing of large numbers of MF. The rapidity of killing is 
believed to be the main driver of these reactions seen at high MF counts. The 
purpose of this study is to assess how imatinib acts as a slow microfilaricide at 
levels (<2,500 MF/mL) that have been safely treated previously with DEC and 
ivermectin. We aim to perform a dose escalation study to identify the minimum 
single oral dose that will be effective as a slow microfiaricidal drug against Loa 
loa. If imatinib is found to be effective and have kinetics which favor slow 
microfilarial killing, then this can serve as the basis for a larger study in which 
patients with very high microfilarial loads would be treated, as this is the at risk 
population in current MDA campaigns. This is a double blind, randomized, pilot 
phase 2 dose-escalation trial. Subjects will receive a dose of imatinib at 200, 400 
or 600 (n = 5 each). Symptoms and blood microfilarial concentration will be 
assessed at baseline, daily for the first 7 days, then weekly for the next 21 days, 
then at 3, 6, and 12 months. These will be compared against an untreated 
placebo-controlled group of 5 subjects who will have the same data collected at 
these respective days. 


Imatinib in loiasis 
Version 10.0 
Page 9 of 34 
1 Background Information and Scientific Rationale 
1.1 Background Information 
The World Health Organization has the goal of eliminating lymphatic filariasis 
(LF) caused by the filarial parasites Wuchereria bancrofti, Brugia malayi, and 
B. timori, and onchocerciasis, caused by the filarial species Onchocerca volvulus, 
by the year 2020. Approximately 157 million individuals are infected with 
organisms that cause either LF or onchocerciasis, together being responsible for 
~6.3 million disability-adjusted life years (DALYs).[1] To this end, millions of 
doses of ivermectin and albendazole have been distributed throughout Africa 
through mass drug administration (MDA) campaigns. Of enormous concern for 
the MDA programs for LF and onchocerciasis in Central and West Africa is 
co-incident Loa loa infection in which Loa-infected individuals with very high 
levels of microfilariae (MF) have had severe neurological adverse events (AEs) 
including encephalopathy and death following ivermectin administration[2]. This 
has led to a cessation of ivermectin-based MDA in areas where Loa loa is 
present. Considered to be relatively non-pathogenic, Loa loa occasionally 
causes transient angioedema and eyeworm (subconjunctival migration of an 
adult parasite); extremely rarely it can cause renal and/or cardiac dysfunction.[3] 
In Loa-endemic areas, no treatment for loiasis is given because of the concern 
for severe reactions with currently available drugs. The reason we are seeking a 
treatment is so that lymphatic filariasis and onchocerciasis can be safely treated 
after Loa loa microfilariae are safely eliminated from the bloodstream. 
Recently, in vitro data has shown that the human stages of B. malayi (MF, L3, 
adult) are susceptible to imatinib-induced filaricidal effects, thought to be due to 
inhibiting an abl-like protein expressed by this filaria which has a high homology 
to the human c-Abl protein, to which it was designed to bind.[4] Moreover, the 
concentration producing 50% inhibition (IC50) found in vitro for MF (6.06 μM) and 
L3 (11.27 μM) were lower than the observed maximum concentration (Cmax, 
13.3 μM) in vivo following a single 600mg oral dose of imatinib.[5] Three 
dimensional modeling of the protein which is found in Loa loa shows that imatinib 
would likely bind to the abl-like protein in the same way.[4] Sequence analysis of 
this abl-like protein found in L. loa, B. malayi, O. volvulus, and W. bancrofti, show 
>98% identity between each other at the projected drug binding site.[4] The 
probability of Loa-related treatment side effects following ivermectin 
administration increases proportionally to the microfilarial loads (non-neurologic 
side effects seen with >8,000 MF/mL,[6] neurologic side effects seen with 
>30,000 MF/mL)[2] Severe side effects begin within 3 days following medication 
administration[7, 8] and do not appear to change with simply using a lower dose 
of ivermectin.[9] Moreover, when treated with ivermectin, MF appear to reliably 
decrease post treatment by 70-100% day 1 following treatment (Herrick et al, 
2017), with a slight increase to 65% by day 3 [10], then falling again thereafter 
[10]. 


Imatinib in loiasis 
Version 10.0 
Page 10 of 34 
1.2 Imatinib 
Imatinib is a small molecule inhibitor which was US Food and Drug 
Administration (FDA)-approved for chronic myelogenous leukemia (CML) in 2001 
which acts on the protein product of the Philadelphia chromosome, Bcr-Abl. 
Single dose administration in healthy volunteer studies (imatinib 400mg) have 
shown a remarkable safety profile although headaches, nausea/vomiting and 
diarrhea have been reported.[5, 11] 
1.3 Rationale 
Given the high homology of the protein between Loa loa abl-like protein, and 
human c-Abl, which imatinib targets, as well as in vitro data suggesting that 
imatinib will have microfilaricidal effects at achievable physiologic doses,[4] this 
study aims to answer the question of whether imatinib has significant 
microfilaricidal effects in vivo. Additionally, this presents both the opportunity to 
explore a drug which may treat this disease, as well as provide a very safe model 
by which we can predict the safety and efficacy of this drug on Loa loa by 
assessing the rapidity in which microfilariae are killed. 
In studies observing treatment reactions in patients with high levels of Loa loa 
microfilaremia, side effects of fever, pruritus, headaches, and arthralgias were 
seen in the first 24-36 hours.[10] Within the first 3 days following treatment 
hematuria, proteinuria, decrease in alkaline phosphatase, increase in white blood 
cell counts, and dramatic changes in eosinophil counts are seen proportional to 
the degree of pre-treatment microfilaremia levels.[10, 12] Thus, we plan to 
evaluate clinical symptoms daily for the first 7 days, expecting to find any clinical 
manifestations pertaining to a treatment reaction to begin prior to day 4 following 
drug administration. Likewise, we will check all of the above mentioned 
laboratory tests daily during for the first 7 days, and again would expect any 
abnormalities related to a treatment reaction to begin prior to day 4 following drug 
administration. One dose of imatinib has not been associated with clinically 
significant laboratory abnormalities or any of the above side effects.[5, 11, 13] 
The primary objective of this study is to model the microfilaricidal effects of 
imatinib in the short-term (days) and long term (weeks-months). Following a dose 
of ivermectin a 70-100% decrease in MF is seen by day 1[14]. Based on both 
efficacy and microfilarial decline we can then pick the most promising appearing 
imatinib dose in order to design a larger trial evaluating efficacy. 
Microfilarial levels will be checked daily for the first week, then weekly for the 
next 3 weeks in order to track the kinetics of the microfilaricidal properties as it is 
currently unknown when the nadir will occur. Likewise, while imatinib may in vitro 
have some sterilizing effects on the adult female worms [15], whether this 
happens in vivo is unknown. Although these subjects live in Loa loa endemic 
areas, the time from infection to appearance of MF in the blood is over 
3 months.[16] Thus, blood microfilariae seen at month 3 following imatinib would 
indicate persistent female fertility and not reinfection. A 6 month blood draw is 
scheduled to assess for durability of the response with the acknowledgement that 


Imatinib in loiasis 
Version 10.0 
Page 11 of 34 
reinfection may occur. Subjects who have previously experienced side effects or 
lab abnormalities following microfilarial killing at high levels of Loa loa 
microfilaremia (>10,000MF/mL) in the first 3 days can experience fevers, 
headaches, fatigue, confusion, arthralgias, and pruritus,[10, 12] which is why we 
will be interviewing and performing a focused physical exam on enrolled subjects 
daily for the first week, and thereafter if the subjects indicate new symptoms. 
Additionally, during these days some subjects may develop proteinuria, 
hematuria, changes in alkaline phosphatase or the white blood cell differential, 
and so safety labs, including CBC with differential, liver enzymes, creatinine, and 
urinalysis will be throughout the first week, then weekly (CBC and MF smear) for 
3 more weeks, then at 3, 6, and 12 months (see Appendix “A: schedule of 
evaluations”). 
2 Study Objectives 
2.1 Primary Objective: To model the short-term microfilaricidal 
kinetics of imatinib against Loa loa for use in designing follow-up studies. 
2.2 Secondary Objectives 
To assess the safety of single dose of imatinib in Loa loa 
2.3 Exploratory Objectives 
To assess laboratory abnormalities associated with potential killing of Loa loa 
microfilariae; and to determine the efficacy of single-dose imatinib as a 
microfilaricide at 1-, 3-, 6-, and 12-month time points. 
3 Study Design 
3.1 Description of the Study Design 
This is a randomized, double blind, placebo-controlled dose escalation pilot 
study. Increasing doses of imatinib will be given to different subjects (each not to 
receive more than 1 dose), and MF change following imatinib will be compared to 
blinded placebo-receiving subjects’ MF concentrations. Halting criteria are 
described in section 11.6. 
Dose Escalation Schedule: 
Group 1 (7 subjects: 5 drug, 2 placebo): 200mg oral (po) imatinib mesylate given 
day 0 of group 1 (G1D0), side effects monitored daily. If no halting criteria (SAE 


Imatinib in loiasis 
Version 10.0 
Page 12 of 34 
or grade 3 or higher AE by CTCAE v5.0) are met by G1D41, group 2 can begin 
the study. 
Group 2 (7 subjects: 5 drug, 2 placebo): 400mg po imatinib mesylate given 
G2D0, side effects monitored daily. If no halting criteria (SAE or grade 3 or higher 
AE by CTCAE v5.0) are met by G2D4, group 3 begins the study. 
Group 3 (6 subjects: 5 drug, 1 placebo): 600mg po imatinib mesylate given 
G3D0, side effects monitored daily. 
Study Endpoints 
3.2 Primary Endpoint 
Percent of baseline Loa loa microfilariae as determined by concentrated 
peripheral blood smear. Daily measurements will be taken the first week, 
followed by measurements at day 14 and day 21. 
3.3 Secondary Endpoints 
Tables of AEs by treatment group including grades of AEs, as defined by CTCAE 
(Common Terminology Criteria for Adverse Events v5.0). 
Percent of baseline Loa loa microfilariae over time (up to 12 months). 
3.4 Exploratory Endpoints 
Exploratory endpoints will include laboratory testing and complete blood count 
with white blood cell differential, as well as urine and stool assessment of 
coincident parasitic infections at multiple time points following imatinib used as a 
microfilaricide. 
Percent of baseline Loa loa microfilariae over time: 1, 3 months (and if needed 6 
and 12 months) 
4 Study Population 
4.1 Rationale for Subject Selection 
Since this is a pilot phase II clinical trial and there is a potential risk for unknown 
AEs, only adults without pre-existing medical conditions, and without chronic 
medication use will be enrolled. Women of childbearing age and breastfeeding 
1For group 1 only, if 5/7 subjects have safely passed Day 4, then the remaining 2 subjects can be 
enrolled at the same time as group 2. 


Imatinib in loiasis 
Version 10.0 
Page 13 of 34 
women will likewise be excluded due to potentially harmful effects of imatinib to 
the fetus/infant as detailed below. 
4.2 Recruitment Plan 
The Centre de Recherche sur les Filarioses et Autres Maladies Tropicales 
(CRFilMT) has played a major role in mapping Loa loa infection in Cameroon. 
As such, many of the districts near Yaoundé are hyperendemic for Loa loa. 
Subjects will be recruited through the district health officers who are responsible 
for particular districts. This pilot study will be conducted in Mbalmayo, a Loa loa 
hyperendemic region in which there is a small but well-equipped hospital and 
outpatient clinic, and where the entire census has recently been performed as 
part of a larger epidemiologic study. 
4.3 Subject Inclusion Criteria 
1. Age > 18 years old and < 65 years 
2. Loa loa microfilaremia >500 MF/mL and <2500 MF/mL at screening visit. 
3. Subject has the capacity to understand the potential risks and benefits and 
consents to protocol indicated blood draws and follow up visits 
Participation of Women: 
Contraception: 
Imatinib is a pregnancy category D drug (see package insert). Spontaneous 
abortions and infant congenital anomalies have been reported during 
postmarketing surveillance. Females of childbearing potential will be excluded. 
4.4 Subject Exclusion Criteria 
1. Women under 45 years of age, or over 45 years of age with a menstrual 
period in the preceding 12 months. 
2. Currently breastfeeding 
3. Currently taking daily medications 
4. Known chronic medical conditions, including but not limited to diabetes, 
renal failure, liver disease, seizure disorder, HIV, malignancy, psychiatric 
disorder, or any conditions which within the investigators’ judgement are 
deemed to be clinically significant. 
5. W. bancrofti serologic positivity against Wb123 
6. O. volvulus serologic positivity against Ov16 
7. HIV by history or clinical signs of HIV/AIDS (e.g. oral thrush, oral/skin 
lesions of Kaposi’s sarcoma, etc.) 
8. Any of the following lab abnormalities: Creatinine >1.5, Platelets 
<100,000/mL, Hemoglobin <12g/dL, alanine aminotransferase or 
aspartate aminotransferase >60 U/L, total bilirubin >1.7mg/dL, 
absolute neutrophil count equal to or less than 1500/mm3. 


Imatinib in loiasis 
Version 10.0 
Page 14 of 34 
9. Any condition that, in the opinion of the PI, may substantially increase the 
risk of participation, including any contraindication to imatinib. 
Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than 
enrollment on observational studies. Study staff should be notified of 
co-enrollment as it may require the approval of the PI. 
4.5 Justification for Exclusion of Special Populations 
Exclusion of Women: 
• Pregnancy: Women who are still menstruating over the preceeding year OR 
are less than age 45 years old are excluded from this study because the 
effects of imatinib on the developing human fetus are potentially teratogenic 
or abortifacient without a clear benefit to the mother. 
• Breastfeeding: Because there is an unknown but potential risk for AEs in 
nursing infants secondary to treatment of the mother with imatinib, women 
who are breastfeeding will be excluded. 
Exclusion of Children: 
Because there are no data regarding AEs in adults for this indication to judge the 
potential risk in children, children are excluded from this study. 
Exclusion of subject > 65 years: 
Because we want subjects without significant comorbidities at this phase, 
subjects older than 65 years will be excluded. The data on the safety at this 
phase will give indication for the inclusion of these subjects for the next phase. 
5 Study Agent/Interventions 
5.1 Disposition and Dispensation 
Study agent and placebo will be a vitamin (folic acid) provided by the NIH Central 
Pharmacy and shipped to the study site according to standard pharmacy 
procedures. An unblinded pharmacist member of the study team (who will not be 
involved in collecting subject information) will be responsible for randomization 
and distribution of the drug and placebo. 
5.2 Formulation and Packaging 
Imatinib is available in the US as an orange oblong tablet in the strength of 
400mg with a central score and is packaged in a bottle. For the 100mg tablet, it is 
provided as a round yellow/orange tablet with a central score. For the purposes 
of blinding these pills will be removed from the bottles and provided (up to 3 tabs 
depending on what arm of the study) to the subjects in an envelope. Placebo folic 
acid pills are yellow/orange oblong and round, although not identical, are similar 
in appearance. They will be packaged in envelopes and delivered in the same 


Imatinib in loiasis 
Version 10.0 
Page 15 of 34 
way to subjects in such a manner that the subject will not be able to identify that 
the placebo pills are slightly different than imatinib. 
5.3 Study Agent Storage and Stability 
Imatinib should be stored at a controlled room temperature of 25°C (77°F), with 
excursions permitted between 15 and 30°C (59 and 86°F). It should be protected 
from moisture. Procedures for ensuring this range of temperature are maintained 
are already in place at the pharmacy and will be continued with daily logs and a 
mercury thermometer. 
5.4 Preparation, Administration, and Dosage of Study Agent 
A physician at the study site will remain unblinded throughout the study and be in 
charge of medication blinding and dispensation, and maintaining study 
supplies/inventory list. This physician will be independent of any study 
assessments. To maintain blinding, any discussion of the treatment assignment 
between the clinicians and this physician is prohibited until the study is 
unblinded, except as may be required to address an immediate serious adverse 
event (SAE) that may be affected by this information. 
Dose Groups: 
Group 1 (7 subjects: 5 drug, 2 placebo): 200mg oral (po) imatinib mesylate given 
day 0 of group 1 (G1D0). 
Group 2 (7 subjects: 5 drug, 2 placebo): 400mg po imatinib mesylate given 
G2D0. 
Group 3 (6 subjects: 5 drug, 1 placebo): 600mg po imatinib mesylate given 
G3D0. 
5.5 Assessment of Subject Compliance with Study Agent 
The study drug is administered as a single dose in the presence of a member of 
the research team. 
5.6 Concomitant Medications and Procedures 
Subjects on scheduled daily medications are excluded. Other non-emergency 
medications taken within the first 4 days following study drug administration 
should be discussed with study team prior to administration. 
6 Study Schedule 
Also see Appendix A: Schedule of Evaluations 
  6.1 Screening (Days −14 to −1) 
A brief interview will be conducted, and if no exclusion criteria are initially met by 
history, informed consent will be obtained. No research related procedure will be 
conducted until informed consent is obtained. Then subjects will then undergo a 


Imatinib in loiasis 
Version 10.0 
Page 16 of 34 
clinical assessment and physical exam, have blood drawn for concentration and 
assessment of Loa loa infection via blood smear, dried blood spots for qPCR (to 
be used if needed), and storage for future studies. All subjects will have blood 
taken to assess for O. volvulus (by Ov16 testing) and W. bancrofti (WB123 
serology) using the SD Bioline Oncho/LF IgG4™ RDT, as well as to perform a 
complete blood count, blood chemistry (creatinine, potassium, sodium), and 
hepatic panel (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase, and bilirubin). If the subject meets the eligibility criteria, 
then they will proceed to baseline. 
6.2 Baseline and Randomization (Day 0) 
On Study Day 0, subjects will undergo blood microfilariae count, complete blood 
count with white cell differential, chemistries (Alkaline phosphatase, ALT, AST, 
bilirubin, creatinine, sodium, potassium), and urinalysis. If subjects are willing, 
urine, and stool specimens will also be collected for possible future analyses. A 
blood spot will also be collected for later Loa loa microfilarial quantification by 
qPCR. A baseline evaluation of symptoms will be conducted, as well as history 
and physical exam (including vital signs). 
After baseline evaluation, subjects will be randomized to either treatment or 
placebo for the current test group (i.e. randomization of 6 [group 3] to 7 [groups 1 
and 2] subjects will occur with each drug escalation minimum of 4 days following 
the previous dose, up to 14 days later). Each group will be allocated a collection 
of sealed envelopes such that 2 randomly selected subjects from each of groups 
1 and 2 will receive placebo and 1 subject will receive placebo from group 3. 
Randomization is being generated by the statistician and randomization codes 
supplied by him to the on-site pharmacist, both whom are unblinded. Each group 
will have 5 subjects receive imatinib. Subjects will be given the drug dose 
assigned to their group or placebo on day 0, and a small volume of blood will be 
drawn 2-4 hours following study drug administration to test for peak imatinib 
levels. 
6.3 Study Phase (Days 1 to 28) 
On D1 (approximately 24 hours later), blood to test an imatinib level will again be 
drawn. For all subjects, daily D1 through D7, and thereafter every 7 days D14 to 
D28, blood smears for microfilariae, blood spots for Loa loa qPCR, complete 
blood count with differential, will be performed, as will a symptom assessment 
(see Appendix C), a targeted history and physical exam, and assessment for any 
drug toxicity. Chemistries (alkaline phosphatase, ALT, AST, bilirubin, creatinine, 
sodium, potassium) will be performed 4 out of the first 7 days, Serum will be 
collected and stored.The targeted physical exam will be performed on D21 and 
thereafter only if symptoms are reported. Urinalysis will be conducted daily 
D1-D7 to assess for proteinuria and hematuria. 


Imatinib in loiasis 
Version 10.0 
Page 17 of 34 
If no halting criteria are met by D4 following drug administration (grade 3 or 
above CTCAE or SAE), the subsequent group will undergo randomization and a 
higher dose will be given. If halting criteria are met after a higher dose of drug 
has been given, halting rules (see Section 11.7) will be followed with suspension 
in enrollment and further doses held until it is deemed safe to continue or it is 
decided the study should discontinue. 
6.4 Follow-up and Final Study Visits 
Subjects will be assessed at 3 months (+/- 7 days) following drug administration, 
and 6 and 12 months (any day of the 6th and 12th month) following drug 
administration. At those times, a blood for microfilarial quantification, blood spots 
for Loa loa PCR, and complete blood count with differential will be performed, as 
will a symptom assessment, and assessment for any drug toxicity. A targeted 
physical exam will be performed only if symptoms are reported. Subjects will 
have the options to provide urine and stool samples at these time points for 
further future analyses. 
6.5 Early Termination Visit 
Subjects who withdraw from the study are not required to complete additional 
visits. These subjects, similarly to those that do complete the trial will be given a 
dose of DEC following confirmation peripheral blood smear is <5000MF/mL. 
6.6 Final disposition for participant 
At the end of the study, after confirmation by concentrated blood smear that 
peripheral blood contains <5000MF/mL, all the participants will receive one dose 
(300 mg) of diethylcarbamazine (DEC) to reduce Loa loa microfilarial levels. 
7 Study Procedures/Evaluations 
7.1 Clinical Evaluations 
A medical history and physical examination to assess potential signs and 
symptoms of Loa loa infection will be performed as part of the baseline 
evaluation. Clinical evaluations at subsequent time points will be targeted and 
focus on the assessment of new symptoms, signs or untoward medical events. 
All of these assessments are both for research as well as clinical safety 
purposes. This includes assessing for complications related to microfilarial death 
(headache, arthralgia, confusion) as well as medication side effect (headache, 
nausea, vomiting, diarrhea). Vital signs, including blood pressure, heart rate, and 
body temperature will be measured as part of all physical examinations, 
according to standard nursing practice. 


Imatinib in loiasis 
Version 10.0 
Page 18 of 34 
7.2 Laboratory Evaluations 
7.2.1 Clinical and Laboratory Evaluations and Specimen Collection 
Blood for routine laboratory testing and for research studies will be obtained by 
venipuncture. Serum samples will be collected and stored at -80 deg C. 
To ensure safety and efficacy in Loa loa microfilariae killing only in enrolling 
subjects, they will be screened for co-infection serology to Wb123 (for W. 
bancrofti) and to Ov16 (for O. volvulus) and excluded if positive. 
Concentrated peripheral blood smears and blood spots for PCR will be collected 
mid-day (10am-2pm). Blood smears will be processed in real time, and qPCR on 
blood spots will be performed at a later time as a verification of what is seen in 
the peripheral smear (particularly at low MF levels). 
Complete blood count with differential and urinalysis will be performed daily 
during week 1 and blood chemistries and hepatic panel will be performed 4 days 
during week 1 when other drugs have had the most impact on these parameters, 
then all but urinalysis (which will not be continued) will be progressively more 
spaced out as the likelihood of finding abnormalities decreases over time from a 
microfilaricide. Serum will be collected for future studies pertaining to immune 
function and/or co-pathogen identification. 
If subjects are willing stool and urine will be collected for future studies pertaining 
to co-pathogens and/or diagnostic test development. 
7.2.2 Specimen Preparation, Handling and Shipping 
Serum samples will be aliquoted and frozen at the CRFilMT and stored at both 
the CRFiLMT or at the NIH at -80oC for future use. Blood spots, stool, and urine 
will be stored at CRFilMT or at NIH for for future use. 
8 Potential Risks and Benefits 
8.1 Potential Risks 
8.1.1 Imatinib 
Imatinib is a small molecule inhibitor which was FDA approved for CML in 2001 
which acts on the protein product of the Philadelphia chromosome, Bcr-Abl. 
Single dose administration in healthy volunteer studies (imatinib 400mg) have 
shown a good safety profile, with headache (53%), nausea (13-43%), vomiting 
(13%), and diarrhea (3%).[5, 11] Although in the case of daily dosing for 
malignancy possible side effects include edema, cytopenias, rash, and extremely 
rarely, death, these have not been reported in healthy volunteers with one dose 
of medication. Therefore, these AEs are very unlikely to occur in this study. 


Imatinib in loiasis 
Version 10.0 
Page 19 of 34 
Imatinib is classified as a pregnancy category D drug (package insert) based on 
animal and human data. There are postmarket reports of spontaneous abortions 
and birth defects from women who have taken imatinib for treatment of 
malignancy. Risk appears to be greatest during the first trimester during 
organogenesis (which protein kinases play a key role in) [17, 18]. Major 
organogenesis occurs from days 13-56 of gestation [19], however using a low 
serum beta-HCG cutoff (10IU/l) detects essentially all pregnancies by day 11-12 
[20-22], thus minimizing these risks by excluding women with detectable levels at 
screening or baseline. However, given the exploratory nature of this study, all 
women of childbearing age will be excluded from this study. 
Imatinib is excreted in breastmilk, therefore women who are breastfeeding are 
excluded from this study. 
There are no risks associated with the placebo. 
8.1.2 Blood draws 
The potential risks of the needlestick for blood drawing include pain, fainting, 
infection and bruising, or a small hematoma. The bruising may last up to 72 
hours. Any hematomas will be treated with local pressure. Infection from the 
needle puncture is rare, but if this does occur, appropriate treatment will be 
given. The total amounts of blood drawn are shown in Appendix B. 
8.1.3 Microfilarial Death 
Rapid killing of high microfilarial loads in Loa loa have been associated with 
pruritus, rash, asthma-like respiratory complications, angioedema, hypotension, 
and, extremely rarely, neurologic complications and death. This study has 
specifically been designed to avoid these complications; given the low Loa loa 
microfilarial loads this is not expected to be a problem. 
8.2Potential Benefits 
Participants may not directly benefit from imatinib therapy. However, subjects 
may receive some benefit if imatinib is able to clear the Loa loa infection. 
Subjects may also benefit from enhanced access to medical care and intensive 
active surveillance for Loa loa infection since they will be getting laboratory 
testing performed both at baseline and throughout the trial. Any illness that may 
have been caused by the study drug will be treated without cost to the 
participants. The information obtained in this study will improve the 
understanding of the use of imatinib in treating people with Loa loa infection. 
Subjects may benefit from treatment with a single dose of DEC. 
9 Research Use of Stored Human Samples, Specimens 
or Data 
• Intended Use: Samples and data collected under this protocol may be 
used to study parasite infections. No genetic testing will be performed. 
Any other research or experimental treatments will be done under this or 


Imatinib in loiasis 
Version 10.0 
Page 21 of 34 
other protocols for which separate signed informed consent documents 
will be obtained. 
• Storage: Access to stored samples will be limited using a locked room or 
freezer, in both Cameroon and Bethesda.  Samples and data will be 
stored using codes assigned by the investigators. Data will be kept in 
password-protected computers. Only investigators will have access to the 
samples and data. 
• Tracking: Samples and data acquired during this study will be tracked 
using the NIH Biological Specimen Inventory System. 
• Disposition at the Completion of the Protocol: 
• In the future, other investigators (both at NIH and outside) may wish 
to study these samples and/or data. In that case, Institutional 
Review Board (IRB) approval must be sought prior to any sharing 
of samples and/or data. Any clinical information shared about the 
sample would similarly require prior IRB approval. 
• At the completion of the protocol (termination), samples and data 
will either be destroyed, or after IRB approval, transferred to 
another existing protocol. 
• Reporting the Loss or Destruction of Samples/Specimens/Data to the 
IRB: 
• Any loss or unanticipated destruction of samples or data (for 
example, due to freezer malfunction) that meets the definition of 
Protocol Deviation and/or compromises the scientific integrity of the 
data collected for the study, will be reported to the NIAID IRB. 
• Additionally, subjects may decide at any point not to have their 
samples stored. In this case, the principal investigator will destroy 
all known remaining samples and report what was done to both the 
subject and to the IRB. This decision will not affect the subject’s 
participation in this protocol or any other protocols at NIH. 
10 Remuneration Plan for Subjects 
The subjects will be reimbursed for participation in this study and 
as compensation for their time. Subjects will be paid 10 000 cfa ($19) for each 
outpatient or inpatient visit since it would lead to an entire day of missed work. 
11 Assessment of Safety 
AEs and other reportable events are defined in NIH Human Research 
Protections Program (HRPP) Policy 801. 
11.1 Toxicity Scale 
The Investigator will grade the severity of each AE according to the “Common 
Terminology Criteria for Adverse Events (CTCAE)” (v 5.0) which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Subjects with documented vital sign, symptom, physical exam, or laboratory evidence of pre-existing 
conditions that are intermittent in nature and that re-occur to the same degree they occurred at 
baseline/screening will not be considered to be having an AE when those same findings re-occur, even if 


Imatinib in loiasis 
Version 10.0 
Page 22 of 34 
there are intervening normal/absent observations. Any worsening in grade from baseline will be reported as 
an AE of the appropriate grade per CTCAE v5. 
11.2 Recording/Documentation 
All AEs occurring from the time the informed consent is signed through the 
specified study follow-up period (i.e. 12 months) will be documented, recorded, 
and reported. All events, both expected/unexpected and related/unrelated will be 
recorded on a source document. Source documents will include progress notes, 
laboratory reports, consult notes, phone call summaries, survey tools, and data 
collection tools. Source documents will be reviewed in a timely manner by the 
research team. All reportable AEs that are identified will be recorded on the 
appropriate case report form (CRF). The start date, the stop date, the severity of 
each reportable event, and the PI’s judgment of the AE’s relationship and 
expectedness to the study agent/intervention will also be recorded on the 
appropriate CRF. If a diagnosis is clinically evident (or subsequently 
determined), the diagnosis rather than the individual signs and symptoms or lab 
abnormalities will be recorded as the AE. Clinical team members will be entering 
patient interview, physical exam findings, and vital sign information directly onto 
tablets with RedCap in the clinic. Laboratory results will be entered by clinical 
and non-clinical team members from source documents into RedCap from the 
laboratory location. Adverse events will be logged into RedCap along with these 
data entry points. 
11.3 Causality 
Causality (likelihood that the event is caused by the study agent(s)) will be 
assessed considering the factors listed under the following categories: 
Definitely Related 
• reasonable temporal relationship 
• follows a known response pattern 
• clear evidence to suggest a causal relationship 
• there is no alternative etiology 
Probably Related 
• reasonable temporal relationship 
• follows a suspected response pattern (based on similar agents) 
• no evidence of a more likely alternative etiology 
Possibly Related 
• reasonable temporal relationship 
• little evidence for a more likely alternative etiology 
Unlikely Related 
• does not have a reasonable temporal relationship 
OR 
• good evidence for a more likely alternative etiology 
Not Related 


Imatinib in loiasis 
Version 10.0 
Page 22 of 34 
• does not have a temporal relationship 
OR 
• 
definitely due to an alternative etiology 
11.4 Reporting Procedures 
11.4.1 Expedited Reporting to the NIAID IRB 
Unanticipated problems, non-compliance, and other reportable events will be 
reported to the NIAID IRB according to Policy 801. 
11.4.2 Annual Reporting to the NIAID IRB 
The following items will be reported to the NIAID and Cameroon IRBs in 
summary at the time of Continuing Review: 
• Serious and non-serious unanticipated problems 
• Expected SAEs that are possibly, probably, or definitely related to the 
research 
• SAEs that are not related to the research 
• All AEs 
• Serious and non-serious protocol deviations 
• Serious, continuing, and minor non-compliance 
• Any trends or events which in the opinion of the investigator should be 
reported 
11.4.3 Pregnancy 
In the rare event that pregnancy does occur on thisthis trial, pregnant subjects 
will be followed for safety and notifications will be made as required by the 
DSMB, NIAID IRB, and Ethics Committee in Cameroon. The subject will be 
advised to notify their health provider of study participation and study agent 
exposure. The subject’s assignment to active study agent or placebo may be 
unblinded to facilitate care and to potentially reduce uncertainty and stress for a 
subject who received placebo. 
Although pregnancy itself is not an AE, events that meet SAE criteria during 
pregnancy, delivery, or in the neonate (eg, congenital anomaly/birth defect) are 
reportable on the CSERF. Of note, women of childbearing age are excluded. 
11.5 Type and Duration of the Follow-up of Subjects 
after Adverse Events 
Subjects who suffer from AEs felt to be related to the administration of imatinib 
will be followed clinically and with laboratory monitoring if needed, until resolution 


Imatinib in loiasis 
Version 10.0 
Page 23 of 34 
of the AE, or until 12 months following drug administration, whichever is first. 
Subjects requiring inpatient treatment as a result of study participation will be 
provided appropriate hospital care as may be indicated. 
11.6 Halting Rules for the Protocol 
Halting the study requires immediate discontinuation of study agent administered 
for all subjects and suspension of enrollment until a decision is made whether or 
not to continue enrollment and study agent administration. 
In the event of any SAE, or an AE equal to or greater than a grade 3 toxicity 
(CTCAE v5.0) the study will be halted (no new enrollments and no further 
administration of imatinib) by the investigators until a decision is made whether or 
not to continue enrollment and drug administration and a report will be submitted 
to the NIAID IRB, DSMB, and the EC in Cameroon. 
The PI will determine if the study should be halted. In addition, the NIAID IRB, 
the DSMB, or the EC may halt the study at any time following review of any 
safety concerns. 
11.6.1 Reporting a Study Halt 
If a halting rule is met, then a description of the AEs or safety issue must be 
reported by the PI, within one business day, to the NIAID IRB, EC, and the 
DSMB by fax or email. 
11.6.2 Resumption of a Halted Study 
The PI, in collaboration with the DSMB, will determine if it is safe to resume the 
study. 
The PI will notify the IRB and the EC of the decision on resumption of the study. 
11.7 Discontinuation of Study 
The study will be discontinued when any SAE felt by the study investigator to be 
related to imatinib administration and/or microfilarial killing due to imatinib 
administration is seen in any of the treatment groups. In this case no further drug 
will be administered, but monitoring and follow up visits, exams, and laboratories 
will be completed for previously enrolled subjects. 
11.8 Withdrawal Criteria for an Individual Subject 
An individual subject will be withdrawn for any of the following: 
• Non-compliance with study procedures to the extent that it is potentially 
harmful to the subject or to the integrity of the study data. 
• The investigator determines that continued participation in the study would 
not be in the best interest of the subject. 


Imatinib in loiasis 
Version 10.0 
Page 24 of 34 
11.9 Replacement of Withdrawn Subjects or Subjects 
who Discontinued Study Agent 
There will be no replacement of subjects who discontinue study given that this is 
a single dose study. However, every attempt will be made to follow up subjects 
who do not present to follow up appointments so that response and side effects 
may be captured. 
11.10 Safety Oversight 
The NIAID Intramural DSMB includes independent experts that do not have 
direct involvement in the conduct of the study and have no significant conflicts of 
interests as defined by NIAID policy. The DSMB will review the study prior to 
initiation and twice a year thereafter. The DSMB may convene additional reviews 
as necessary. The DSMB will review the study data to evaluate the safety, 
efficacy, study progress, and conduct of the study. All SAEs and all UPs will be 
reported by the PI to the DSMB at the same time they are submitted to the IRB. 
The PI will notify the DSMB of any cases of intentional or unintentional unblinding 
as soon as possible. The PI will notify the DSMB at the time halting criteria are 
met and obtain a recommendation concerning continuation, modification, or 
termination of the study. The PI will submit the written DSMB summary reports 
with recommendations to the IRB. 
12 Site Monitoring Plan 
As per International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) 5.18, clinical protocols are required to be adequately monitored by the 
study sponsor. Monitors under contract to the Office of Clinical Research Policy 
and Regulatory Operations (OCRPRO)/NIAID will visit the clinical research site to 
monitor aspects of the study in accordance with the appropriate regulations and 
the approved protocol. The objectives of a monitoring visit will be: 1) to verify the 
existence of signed informed consent documents and documentation of the 
informed consent process for each monitored subject; 2) to verify the prompt and 
accurate recording of all monitored data points, and prompt reporting of all SAEs; 
3) to compare abstracted information with individual subjects’ records and source 
documents (subjects’ charts, laboratory analyses and test results, physicians’ 
progress notes, nurses’ notes, and any other relevant original subject 
information); and 4) to help ensure investigators are in compliance with the 
protocol. The monitors also will inspect the clinical site regulatory files to ensure 
that regulatory requirements (Office for Human Research Protections-OHRP), 
and applicable guidelines (ICH-GCP) are being followed. During the monitoring 
visits, the investigator (and/or designee) and other study personnel will be 
available to discuss the study progress and monitoring visit. 
The investigator (and/or designee) will make study documents (e.g., consent 
forms) and pertinent hospital or clinical records readily available for inspection by 
the local IRB, the site monitors, and the NIAID staff for confirmation of the study 
data. 


Imatinib in loiasis 
Version 10.0 
Page 25 of 34 
A specific protocol monitoring plan will be discussed with the Principal 
Investigator and study staff prior to enrollment. The plan will outline the frequency 
of monitoring visits based on such factors as study enrollment, data collection 
status and regulatory obligations. 
13 Statistical Considerations 
13. 1 Study Hypotheses 
The primary purpose of this study is to learn about the pharmacokinetics of Loa 
loa MF after treatment with different doses of imatinib. Since this drug has not 
been studied in patients with Loa loa microfilariae before (except one patient, see 
the next section), the data from this study will help to get an idea about how the 
drug affects the Loa loa microfilariae over time. An important issue is how fast 
the Loa loa MF are killed in the blood in the short term, since rapid killing can 
lead to safety issues when the baseline Loa loa MF count is large (much greater 
than the upper bound of the inclusion criteria of 2500 MF/mL). Another issue is 
the longer term kinetics, since we want to Loa loa MF to be killed slowly. 
13.2 Sample Size Justification 
This is a pilot study to help in designing a follow-up study. Currently, only one 
patient with Loa loa parasite infection has gotten imatinib. That patient received a 
600mg dose and had no severe adverse events [23]. The MF/ml measurements 
were 2250 MF/ml (day 0), 719 (day 4), 150 (day 6), and 392 (day 11).  In terms 
of the percent reduction from baseline the values are 68% reduction (day 4), 93% 
(day 6) and 83% (day 11). In this one patient, the drug showed promise because 
it reduced the MF/ml values, but they did not reduce as quickly as ivermectin or 
DEC (70-100% day 1). Because it is only one patient, we have no data on 
subject-to-subject variability. The sample sizes of 5 on the three dose groups 
(doses 200mg, 400mg, and 600mg) will allow for estimation of variability across 
subjects and at different doses. It will also give better estimates on the effect of 
the dose over time in the population. 
In terms of safety, if there is a SAE that occurs in 37% of the population, then we 
have a 90% probability of seeing one subject with that event in a group of size 5. 
If the rate of SAEs in the population is 14%, then we have a 90% probability of 
seeing one subject with that event in a group of size 15 (the total number of 
subjects that got any dose). 
13.3 Final Analysis Plan 
 
Study Endpoints 
Primary: 
Percent of baseline Loa loa microfilariae as determined by concentrated 
peripheral blood smear. Daily measurements will be taken the first week, 


Imatinib in loiasis 
Version 10.0 
Page 26 of 34 
followed by measurements at day 14, day 21, day 28 (month 1), and 3 months 
(and if needed 6 and 12 months). 
Secondary: 
1. Tables of AEs by treatment group including grades of AEs, as defined by 
CTCAE v5.0 
2. Percent of baseline Loa loa microfilariae over time (up to 12 months). 
One of the primary pre-specificed safety concerns with treatment of Loa loa is 
rapid killing of the Loa loa MF in patients with high baseline Loa loa MF. We 
begin with a linear model on a log transformation of the primary endpoint, with 
different effects over time for the different dose groups. We include a baseline 
subject effect for each subject, so that we are primarily modeling the percent 
reduction from baseline. A sandwich estimator of variance will be used to 
account for the within subject correlation. The longer term effects of the drug are 
also of interest. Since imatinib has not been given in Loa loa patients before we 
will allow flexibility in model building. We will likely start with a linear model on the 
log10(percent of baseline Loa loa MF) with time as a linear factor and effects for 
dose. We may explore other linear models on the same response using 
segmented line regression with possible dose by time interactions. These models 
will help inform any further studies of imatinib in the treatment of Loa loa. 
Exploratory Analyses: 
The exploratory objective for this study is to assess laboratory abnormalities 
associated with potential killing of Loa loa microfilariae. We may build some 
generalized linear models at different points in time to see if the log of the 
proportion of baseline Loa loa MF (or some other transformation of those MF 
levels) are predictive of different laboratory values. Care will be taken so that the 
final model does not overfit the data, or that the variability of the final results 
properly account for the model building process. As an example of the latter, we 
could run a boostrap procedure that repeats the model selection process and 
gives a proportion of the bootstrap data sets that predict certain effects. 
Handling of Missing and Spurious Data: 
For the AE analyses, every effort will be made to prevent missing data. Because 
the treatment is only one dose, if a subject drops out after getting treatment, the 
subject will be encouraged to continue to report AEs for the duration of time that 
they would have remained in the study. 
For the percent change of MF analyses, if some responses are missing, then 
there are two approaches. (1) If the cause of the missingness is likely to be 
unrelated to the response, the we will simply remove that subject from the 
analysis. (2) If the cause of the missingness is probably related to the response, 
and there are a substantial number of missing values, then we will run some 
sensitivity analyses, where the missing response is replaced by either (i) the best 
response (in terms of making the treatment look efficacious), or (ii) the worst 
response, or (iii) some intermediary predicted response. These sensitivity 


Imatinib in loiasis 
Version 10.0 
Page 27 of 34 
analyses will give a range of possible values for what the result would have been 
if there had been no missingness. 
13.4 Planned Interim Analyses 
The purpose of the interim analysis is to determine if, after all subjects have had 
treatment and their 3-month visit, it is likely that any future 6- and 12-month visits 
will give us information that is useful enough to be worth the effort of collecting 
that data. 
Such long-term follow-up will be useful if, in a substantial portion of subjects, the 
effects of imatinib continue to be active after 3 months. A suspected trajectory of 
the effect of a single dose of imatinib is that the MF counts will decrease to a 
nadir, and then climb up again, indicating that the imatinib is no longer active. We 
will assume it is useful to continue following subjects if by the 3-month visit more 
than 2 subjects who received imatinib (out of the total of 15) have not apparently 
reached their nadir yet. 
A subject will be said to have reached their nadir by 3 months if the following 
occurs: 
• a reduction of MF to less than 20% of pre-treatment levels is subsequently 
followed by a MF rise to or above 40% of pretreatment levels; 
• however, if after the MF dropping to 20% of pretreatment levels, then 
rising to 40% there is at least 1 MF count below 40% of pre-treatment 
levels and the trend appears decreasing, then the subject will be 
considered to not have reached their nadir. A decreasing trend is defined 
as a slope of less than 0 of the least squares fit line predicting MF count 
over time, based only on the MF counts from the first MF count at or 
above 40% of pre-treatment levels until the MF count at the 3-month visit. 
The interim analysis will occur after the last enrolled subject has had his or her 3- 
month visit, but before that subject had his or her 6-month visit. Because the 
biostatistician and the pharmacist are the only 2 unblinded members of the 
research team, they will be the only 2 members able to help with the 
performance of these interim analyses. All other study members will remain 
blinded until the study end. 
13.5 Safety Analysis 
The safety analysis will be primarily descriptive, listing tables of AEs. Of 
particular concern are safety events possbibly related to imatinib or reactions to 
microfilarial death. 


Imatinib in loiasis 
Version 10.0 
Page 28 of 34 
14 Ethics/Protection of Human Subjects 
14.1 Informed Consent Process 
Informed consent is a process where information is presented to enable persons 
to voluntarily decide whether or not to participate as a research subject. It is an 
on-going conversation between the human research subject and the researchers 
which begins before consent is given and continues until the end of the subject's 
involvement in the research. Discussions about the research will provide 
essential information about the study and include: purpose, duration, 
experimental procedures, alternatives, risks and benefits. Subjects will be given 
the opportunity to ask questions and have them answered. 
Consent will be administered in French and explained in the subject’s local 
dialect. The subjects will sign two copies of the informed consent document prior 
to undergoing any research procedures, one which they will retain and the other 
will be kept with the study. The researcher will document the signing of the 
consent form in the subject’s medical record. The rights and welfare of the 
subjects will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. The 
subjects may withdraw consent at any time throughout the course of the trial. 
14.2 Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and 
local law. The study monitors and other authorized representatives of the 
Sponsor may inspect all documents and records required to be maintained by the 
Investigator, including but not limited to, medical records. Records will be kept 
locked and all computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission 
of the subject, except as necessary for monitoring by IRB, [the FDA], the NIAID, 
the OHRP, or the sponsor’s designee. 
15 Data Handling and Record Keeping 
15.1Data Capture and Management 
Study data will be maintained in CRFs and collected directly from subjects during 
study visits and telephone calls, or will be abstracted from subjects’ medical 
records. Source documents include all recordings of observations or notations of 
clinical activities and all reports and records necessary to confirm the data 
abstracted for this study. Data entry into RedCap/DataFax electronic database 
will be performed by authorized individuals. The Investigator is responsible for 
assuring that the data collected are complete, accurate, and recorded in a timely 
manner. 


Imatinib in loiasis 
Version 10.0 
Page 29 of 34 
15.2 Record Retention 
The investigator is responsible for retaining all essential documents listed in the 
ICH GCP Guideline. Study records will be maintained by the PI in accordance 
with CFR 312.62 and in compliance with institutional, IRB, state, and federal 
medical records retention requirements, whichever is longest. All stored records 
will be kept confidential to the extent required by federal, state, and local law. 
Should the investigator wish to assign the study records to another party and/or 
move them to another location, the investigator will provide written notification of 
such intent to OCRPRO/NIAID with the name of the person who will accept 
responsibility for the transferred records and/or their new location. Destruction or 
relocation of research records will not proceed without written permission from 
OCRPRO/NIAID. 
The consent will be administered in French by a local team member. Participant 
will sign or mark with an "X" on 2 copies, and will retain one for themselves and 
one will be kept on permanent record. 
Scientific References 
1. 
Fenwick A. The global burden of neglected tropical diseases. Public 
Health 2012; 126(3): 233-6. 
2. 
areas SwgosaeiLle. Report of a Scientific Working Group on Serious 
Adverse Events following Mectizan(R) treatment of onchocerciasis in Loa 
loa endemic areas. Filaria J 2004; 2 Suppl 1: S2. 
3. 
Takougang I, Meli J, Lamlenn S, Tatah PN, Ntep M. Loiasis--a neglected 
and under-estimated affliction: endemicity, morbidity and perceptions in 
eastern Cameroon. Annals of tropical medicine and parasitology 2007; 
101(2): 151-60. 
4. 
O'Connell EM, Bennuru S, Steel C, Dolan MA, Nutman TB. Targeting 
Filarial Abl-like Kinases: Orally Available, Food and Drug Administration- 
Approved Tyrosine Kinase Inhibitors Are Microfilaricidal and 
Macrofilaricidal. J Infect Dis 2015. 
5. 
Parrillo-Campiglia S, Ercoli MC, Umpierrez O, et al. Bioequivalence of two 
film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, 
single-dose, fasting, two-period, two-sequence crossover comparison in 
healthy male South American volunteers. Clinical therapeutics 2009; 
31(10): 2224-32. 
6. 
Gardon J, Gardon-Wendel N, Demanga N, Kamgno J, Chippaux JP, 
Boussinesq M. Serious reactions after mass treatment of onchocerciasis 
with ivermectin in an area endemic for Loa loa infection. Lancet 1997; 
350(9070): 18-22. 
7. 
Twum-Danso NA. Loa loa encephalopathy temporally related to ivermectin 
administration reported from onchocerciasis mass treatment programs 
from 1989 to 2001: implications for the future. Filaria J 2003; 2 Suppl 1: 
S7. 


Imatinib in loiasis 
Version 10.0 
Page 30 of 34 
8. 
Twum-Danso NA. Serious adverse events following treatment with 
ivermectin for onchocerciasis control: a review of reported cases. Filaria J 
2003; 2 Suppl 1: S3. 
9. 
Kamgno J, Pion SD, Tejiokem MC, Twum-Danso NA, Thylefors B, 
Boussinesq M. Randomized, controlled, double-blind trial with ivermectin 
on Loa loa microfilaraemia: efficacy of a low dose (approximately 25 
microg/kg) versus current standard dose (150 microg/kg). Trans R Soc 
Trop Med Hyg 2007; 101(8): 777-85. 
10. 
Ducorps M, Gardon-Wendel N, Ranque S, et al. [Secondary effects of the 
treatment of hypermicrofilaremic loiasis using ivermectin]. Bulletin de la 
Societe de pathologie exotique (1990) 1995; 88(3): 105-12. 
11. 
Kim KA, Park SJ, Kim C, Park JY. Single-dose, randomized crossover 
comparisons of different-strength imatinib mesylate formulations in healthy 
Korean male subjects. Clinical therapeutics 2013; 35(10): 1595-602. 
12. 
Boussinesq M, Gardon J, Gardon-Wendel N, Chippaux J-P. Clinical 
picture, epidemiology and outcome of Loa-associated serious adverse 
events related to mass ivermectin treatment of onchocerciasis in 
Cameroon. Filaria journal 2003; 2 Suppl 1: S4-S. 
13. 
Peng B, Dutreix C, Mehring G, et al. Absolute bioavailability of imatinib 
(Glivec) orally versus intravenous infusion. Journal of clinical 
pharmacology 2004; 44(2): 158-62. 
14. 
Herrick JA, Legrand F, Gounoue R, et al. Posttreatment Reactions After 
Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa 
Infection. Clinical infectious diseases : an official publication of the 
Infectious Diseases Society of America 2017; 64(8): 1017-25. 
15. 
O'Connell EM, Kamenyeva O, Lustigman S, Bell A, Nutman TB. Defining 
the target and the effect of imatinib on the filarial c-Abl homologue. PLoS 
neglected tropical diseases 2017; 11(7): e0005690. 
16. 
Orihel TC, Eberhard ML. Loa loa: development and course of patency in 
experimentally-infected primates. Tropical medicine and parasitology : 
official organ of Deutsche Tropenmedizinische Gesellschaft and of 
Deutsche Gesellschaft fur Technische Zusammenarbeit (GTZ) 1985; 
36(4): 215-24. 
17. 
Lambertini M, Peccatori FA, Azim HA, Jr. Targeted agents for cancer 
treatment during pregnancy. Cancer Treat Rev 2015; 41(4): 301-9. 
18. 
NTP Monograph: Developmental Effects and Pregnancy Outcomes 
Associated With Cancer Chemotherapy Use During Pregnancy. NTP 
monograph 2013; (2): i-214. 
19. 
DeSesso JM, Williams AL, Ahuja A, Bowman CJ, Hurtt ME. The placenta, 
transfer of immunoglobulins, and safety assessment of 
biopharmaceuticals in pregnancy. Critical reviews in toxicology 2012; 
42(3): 185-210. 
20. 
Huang X-y, Zhang Y-n, Yu H-q. Serum Beta-hCG of 11 Days after Embryo 
Transfer to Predict Pregnancy Outcome. Journal of Reproduction and 
Contraception 2007; 18(3): 213-9. 


Imatinib in loiasis 
Version 10.0 
Page 31 of 34 
21. 
Poikkeus P, Hiilesmaa V, Tiitinen A. Serum HCG 12 days after embryo 
transfer in predicting pregnancy outcome. Human reproduction (Oxford, 
England) 2002; 17(7): 1901-5. 
22. 
Lenton EA, Neal LM, Sulaiman R. Plasma concentrations of human 
chorionic gonadotropin from the time of implantation until the second week 
of pregnancy. Fertility and sterility 1982; 37(6): 773-8. 
23. 
O'Connell EM, Nutman TB. Reduction of Loa loa Microfilaremia with 
Imatinib - A Case Report. N Engl J Med 2017; 377(21): 2095-6. 


Imatinib in loiasis 
Version 10.0 
Page 32 of 34 
Appendix A: Schedule of Evaluations 
Evaluation 
Screeni 
ng 
(-14 to 
-1 
days) 
Base 
line 
(Day 
0) 
D 
1 
D 
2 
D 
3 
D 
4 
D 
5 
D 
6 
D 
7 
D 
1 
4 
D 
2 
1 
D 
2 
8 
3 Mo 
(D84 
-98) 
6 Mo 
12 Mo 
Medical/Medication History 
X 
X 
X 
Clinical Assessment 
(including symptom 
assessment) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
X 
a 
Xa 
Xa 
Xa 
Informed Consent 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WBC differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatic panel (ALT, AST, 
Alk phos, bilirubin) 
X 
X 
X 
X 
X 
Chemistry (Sodium, 
potassium, creatinine) 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
Concentrated blood smear 
for MF and/or calibrated 
thick smear 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imatinib drug level 
Xc 
Xd 
Ov16/WB123 IgG4 serology 
(for O. volvulus/W.bancrofti) 
X 
Blood spot 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collectionb 
X 
X 
X 
X 
Stool collectionb 
X 
X 
X 
X 
Serum collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alk phos = alkaline phosphatase; ALT = alanine transaminase; AST =aspartate transaminase; CBC = 
complete blood count;; D = day; Mo = month; MF = microfilariae; PCR = polymerase chain reaction; 
WBC = white blood cell; X = to be performed. 
a 
Only performed if the subject indicates symptoms. 
b 
Optional (subjects not required to give these samples to remain in study). 
c 
2-4 hours post imatinib/placebo dose. 
d 
24 hours postdose. 


Imatinib in loiasis 
Version 10.0 
Page 33 of 34 
Appendix B: Blood Volumes for Specimen Collection 
Evaluations 
Study Schedule 
Visit 
Screening Baseline 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
3 
Month 
Follow 
up1 
13 
6 
Month 
Follow- 
up5 
14 
12 
Month 
Follo 
w-up5 
Week of 
Study 
-2 to -1 
Wk 0 
W1 
W1 
W1 
W1 
W1 
W1 
W1 
W2 
W3 
W4 
W13 
(12- 
14) 
W26 
W52 
Day of Study 
-14 to -1 
4D 0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D14 
D21 
D28 
91 (84- 
98) 
~D178 
D 365 
Clinical 
CBC 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Chemistry/LF 
4 
4 
4 
4 
4 
MF smear 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Ov16/Wb123 
<1 
Research 
Blood spot 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Serum 
storage 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Imatinib blood 
level 
0 
2 
2 
2Daily 
Volume (mL) 
10 
13 
13 
7 
7 
11 
7 
7 
7 
7 
7 
7 
7 
7 
7 
3Cumulative 
Volume (mL) 
10 
23 
36 
43 
50 
61 
68 
75 
86 
93 
100 107 
114 
121 
128 
1 3 months (+/- 1 week) following imatinib administration 
2Per NIH MEC Policy M95-9, maximum blood volumes drawn for research purposes for pediatric 
subjects: no more than 5 mL/kg in a single day, and no more than 9.5 mL/kg may be drawn over 
any eight-week period. Exceptions to this policy shall be approved by the IRB. 
3Per NIH MEC Policy M95-9, maximum blood volumes drawn for research purposes for an adult 
subject (aged 18 years or older) may not exceed: 10.5 mL/kg or 550 mL, whichever is smaller, 
over any eight week period. Exceptions to this policy shall be approved by the IRB. 
4 Day 0 evaluations are the baseline for subsequent safety assessments. 
5 Follow up visit can be conducted any day of that month following enrollment. 


Imatinib in loiasis 
Version 10.0 
Page 34 of 34 
Appendix C: Symptom/signs assessment 
Symptom 
Yes/No Date 
started 
Date 
ended 
Description 
Nausea 
Y 
N 
Vomiting 
Y 
N 
Headache 
Y 
N 
Fatigue 
Y 
N 
Joint Pain 
Y 
N 
Muscle Pain 
Y 
N 
Muscle Cramps 
Y 
N 
Edema, facial 
Y 
N 
Edema, 
extremity 
Y 
N 
Rash or 
Hyperpigmentat 
ion 
Y 
N 
Mouth ulcers 
Y 
N 
Decreased 
appetite 
Y 
N 
Fever 
Y 
N 
Rhinorrhea 
Y 
N 
Pruritus 
Y 
N 
Difficulty 
breathing 
Y 
N 
Dizziness 
Y 
N 
Fecal 
incontinence 
Y 
N 
Urine 
incontinence 
Y 
N 
Confusion 
Y 
N 


Imatinib in loiasis 
Version 10.0 
Page 108 of 

ICF_001.pdf: 
 
 
Consent to Participate in a Research Study 
 
 
 
NIAID Protocol #:  
16-I-N042 
 
Principal Investigator:  
Elise O’Connell, MD (Tel: 301-761-5413) 
 
Co-Principal Investigator: Joseph Kamgno, MD, PhD (Tel: 00237-22-20-24-42) 
 
Accountable Investigator: Thomas Nutman, MD (Tel: 301-496-5399) 
 
Sponsors:   
 
Centre de Recherche sur les Filarioses et Autres Maladies 
Tropicales (CRFilMT) 
 
 
 
 
Yaoundé, Cameroon 
 
National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH),  
Bethesda, MD, USA 
 
Site:  
 
 
Mbalmayo, Cameroon 
 
 
 
GENERAL INFORMATION 
We invite you to participate in a research study called “A double-blinded, randomized, 
placebo-controlled dose escalation study to examine the efficacy and microfilaricidal 
kinetics of imatinib for the treatment of Loa loa (A pilot study).” The study is sponsored 
by the Centre de Recherche sur les Filarioses et Autres Maladies Tropicales in 
Cameroon and the National Institutes of Health of the United States of America. 
Participation in this study is voluntary. Before you decide to participate, please take as 
much time as you need to ask any questions and discuss this study with anyone, 
including your family and friends. 
 
BACKGROUND/PURPOSE OF STUDY 
Many people who live in west or central Africa are at risk for infection from a very small 
worm called Loa loa. This parasite is also called an African eye worm. The adult worms 
produce baby worms called microfilariae, which live in the blood. Loa loa infection can 
cause itching, swelling, and extremely rarely problems with the kidneys, eyes, and 
heart. Because this infection is usually not serious, patients in Cameroon usually do not 
seek treatment. However, infection with Loa loa can cause serious problems in people 


 
 
Version 7 April 17, 2019 
 
2 
who are being treated for infections with other parasites. Therefore, we are looking to 
make a new safe and effective way to treat Loa loa infection. 
The purpose of this research study is to find out if a drug called imatinib can treat Loa 
loa infection. We want to see if imatinib, an orally administered pill, is effective at slowly 
killing the Loa loa worms because killing the worms too quickly may cause severe side 
effects. Imatinib is an approved drug to treat certain types of cancer. This study will be 
the first time that it is being tested for Loa loa infection. We will test three different doses 
of imatinib in people with non-severe Loa loa infections (microfilarial counts less than 
2500/mL). It is important to know that you will only be given one dose of either imatinib 
or an inactive agent called a placebo. Because we cannot predict ahead of time how 
Loa loa infections will respond to imatinib, we need to study several doses to learn how 
much might be needed to safely help treat infection with Loa loa. 
 
STUDY PARTICIPANTS 
If you are between 18 and 65 years old and have a non-severe Loa loa infection but are 
otherwise healthy then you can take part in this study. Women of childbearing potential 
are not eligible to participate. We will recruit 20 people for this study. 
PROCEDURES EXPLAINED 
You will be in this study for 12 months. There are a total of 15 study visits to the clinic 
site. Each visit should take approximately 2 hours. The first visit is called the screening 
visit, and the purpose is to make sure that you are eligible to take part in this study. We 
will give you a physical exam and evaluate the severity of your infection. We will ask 
you about how you are feeling and if you have had any illness recently. We will collect 
blood from a vein in your arm to count your blood cells, see if your organs are working 
well, measure your Loa loa infection, and make sure that you are not infected by certain 
other parasites. A blood sample will also be drawn so we can do laboratory tests on it in 
the future. Because imatinib may be harmful to the developing fetus, you cannot 
participate in this study if you are of childbearing age or breastfeeding. 
Within 14 days after your screening visit if you are eligible for the study, you will return 
to the clinic for your baseline visit. You will have another physical and we will ask you 
about how you are feeling and if you have had any medical problems since we last saw 
you. We will collect blood and urine for laboratory tests. You also have the option to 
provide samples of blood, urine, and stool so we can do laboratory tests on them in the 
future. This is voluntary so you may decline to provide these samples and still 
participate in the study. If you had a pregnancy test more than 2 days before this visit, 
then you will have another at this visit to confirm that you are not pregnant. 
You will then receive a single dose pill of either imatinib or a placebo. The placebo will 
be a vitamin pill that looks like imatinib but does not contain any drug. Researchers use 
a placebo to see if a study drug is more or less safe or effective than not taking 
anything. Whether you receive imatinib or placebo will be decided randomly. This is like 


 
 
Version 7 April 17, 2019 
 
3 
deciding by drawing lots. Fifteen people will receive imatinib and five people will receive 
placebo. Until the end of the study, neither you nor the study team will know if you are 
receiving imatinib or placebo. Which dose of imatinib you get will depend on when you 
join the study. If you join earlier then you will get the lower doses or placebo, and if you 
join later then you will receive the higher doses or placebo. About 2 to 4 hours after you 
take imatinib or placebo, we will collect another sample of blood for more laboratory 
tests. 
You will return to the clinic every day for the next week, and then once per week for the 
3 weeks after that. At all visits, you will have a physical and we will ask you how you are 
feeling. We will collect blood for laboratory tests at all visits, and we will collect urine for 
laboratory tests during the first week. You will also have the option to provide blood 
samples so we can do laboratory tests on them in the future. 
You will return to the clinic for follow-up visits at 3, 6, and 12 months after you have 
taken imatinib or placebo. As with the previous visits, you will have a physical exam, we 
will ask you how you are feeling, and we will collect blood for laboratory tests. At the 6 
and 12-month visits, you also have the option to provide samples of blood, urine, and 
stool so we can do laboratory tests on them in the future. 
If you develop side effects from taking imatinib, then we will treat you for those side 
effects according to the standard of care in Cameroon. You will be finished with the 
study after your 12-month visit. 
 
RISKS/DISCOMFORTS EXPLAINED 
The drug that we are testing in this study, imatinib, is approved by the United States 
Food and Drug Administration for the treatment of some types of cancer. Side effects of 
imatinib that have been reported by healthy volunteers who took a single dose of the 
drug are headache, nausea, vomiting, and diarrhea.  
Cancer patients who take imatinib every day for an extended period of time have side 
effects that include rashes, swelling, and lowered blood cell counts. Some have had 
more severe side effects that include death. Because you will only take imatinib one 
time, it is thought to be unlikely that you will have these same side effects.  
Imatinib can harm the developing fetus if you take it when you are pregnant. There have 
been patients who took imatinib while pregnant who lost their pregnancies or had 
children with birth defects. To be safe, you cannot participate if you are a woman of 
childbearing potential (younger than age 45 or menstrual period in the last year) or are 
breastfeeding. 
If imatinib kills the worms in your body too quickly, then you may get rashes, itching, 
swelling, problems with breathing, low blood pressure, and extremely rarely, 
complications with the nervous system or death. However, because you have a non-


 
 
Version 7 April 17, 2019 
 
4 
severe infection, we expect that these side effects are very unlikely to happen in this 
study.  
There are no risks associated with the placebo. 
It is possible that your Loa loa may get worse while you are participating in this study.   
Blood draws may cause pain and bruising and, rarely, infection. Sometimes drawing 
blood causes people to feel lightheaded or even to faint. 
There may be additional risks to participating in this study that are currently unknown. 
You will be told about new findings that develop during the course of the study that may 
change your willingness to participate. 
 
EXPLANATION OF POTENTIAL BENEFITS 
You may not directly benefit from this study. If you do receive imatinib instead of 
placebo, then imatinib may help to treat your Loa loa infection, but it might not.  Even if 
it treats your Loa loa infection you may not feel any different or better (often people do 
not have symptoms of infection). You may also benefit from having medical 
examinations during the course of the study. Additionally, the knowledge gained from 
this study may help other individuals in the future. 
 
COMPENSATION 
You will receive 10000 cfa for each visit as compensation for your time. The initial 
screening visit will not be compensated. 
 
STORED SAMPLES 
We would like to store samples of blood, urine, and stool in case there are additional 
tests we wish to perform in the future. These stored samples will be used only for 
studies related to parasite infection or your immune system. Samples will be stored at 
either the NIH in the United States or CRFilMT in Cameroon. All future studies must first 
be approved by ethics committees at the NIH in the United States and at CRFilMT in 
Cameroon. Ethics committees oversee medical research studies to protect participants’ 
rights and welfare.  
Samples will be labeled with a code that will link you to your blood, urine, and/or stool 
sample and will be accessed by study investigators only. We will keep any information 
that can be traced back to you as private as possible. Other investigators may want to 
study your stored samples. If so, then the study team may send your samples to them 


 
 
Version 7 April 17, 2019 
 
5 
without any information that can identify you. The study team may also share 
information such as your gender, age, health history, or ethnicity.  
Investigators will use your samples only for research. We will not sell them. Future 
research that uses your samples may lead to new products, but you will not receive 
payment for these products. Some future studies may need health information (such as 
smoking history or present health status) that we do not already have. If so, the study 
team will contact you for this information. 
In general, future research that uses your samples will not help you, but it may help us 
learn about parasite infections or related conditions. This research may also help us 
learn how to prevent or treat these conditions. 
The greatest risk is that someone may take information from your medical records 
without your permission. The chances of this happening are very low.  
By agreeing to participate in this study, you do not waive any rights that you have 
regarding access to and disclosure of your records. Whether or not you agree to let us 
store your samples, you may still participate in other studies conducted by the NIH or 
CRFilMT. Even if you agree now to let us store your samples, you can change your 
mind later. If you do, please contact us and say that you do not want us to use your 
samples for future research. 
 
ALTERNATIVES TO PARTICIPATING IN STUDY 
If you do not wish to participate in this study then you are free to decline. 
 
MAKING YOUR CHOICE 
You are free not to take part in this study if you do not want to. If you wish to withdraw 
from the study, then you may do so at any time. Refusing to take part will not affect your 
current or future medical care in any way at the study site clinic in Mbalmayo. If you 
decide to withdraw from the study later, then please inform any member of the study 
team. You will otherwise be a part of the study until you complete the 12-month study 
period. 
 
CONDITIONS FOR REMOVAL FROM STUDY 
You may be removed from the study without your consent if you are unable or unwilling 
to keep scheduled study visit appointments, or if for any reason that study investigators 
determine that participation in the study is placing you at undue risk. 


 
 
Version 7 April 17, 2019 
 
6 
CONFIDENTIALITY 
We will keep the study information private. All files with information that could identify 
you will be kept in locked cabinets. Samples of blood, urine, and stool that are collected 
from you will be marked with a number that tells the study team that it is your blood, 
urine, or stool. These samples will not be marked with your name. However, we cannot 
guarantee absolute confidentiality. People responsible for making sure that the research 
is done properly may look at your study records. These might include people or their 
representatives from CRFilMT or the NIH. All of these people or their representatives 
will also keep your identity private. A description of this clinical trial will be available on 
http://www.Clinicaltrials.gov, as required by U.S. Law. This web site will not include 
information that can identify you. At most the Web site will include a summary of the 
results. You can search this website at any time. 
 
NEW FINDINGS WILL BE DISCUSSED 
The findings of this study may be reported at meetings or in medical journals, but your 
name will not be used in the report. Although the specific information we learn about 
you will not be shared with anyone except the study investigators, the NIH, and its 
authorized representatives, absolute confidentiality cannot be guaranteed. A member of 
the study team will discuss any new findings related to your health or that may affect 
your willingness to participate in this study. If you have any concerns about your 
participation in the study, please feel free to discuss it with a member of the study team 
at any time. 
 
LIST OF CONTACTS 
If you want to speak to anyone about this research study or you think you have been 
hurt by taking part in this study, you should tell the study team (a member of the team 
will be present at the clinic each day during the study). They will ask the Principal 
Investigators, Dr. Elise O’Connell or Dr. Joseph Kamgno, to talk to you. You can also 
ask questions in the future, if you do not understand something that is being done. 
 
DO YOU HAVE ANY QUESTIONS ABOUT PARTICIPATION IN THIS STUDY? 
If you have questions or concerns at a later date, you may speak with one of our staff or 
you can call Dr. Joseph Kamgno of CRFilMT at 00237-22-20-24-42. 
If you agree to participate in this study, then please sign or put your thumb or fingerprint 
below.  
 


 
 
Version 7 April 17, 2019 
 
7 
___________________________________ 
 
 
________________ 
Subject Signature, Finger or Thumb Print  
 
           Date  
 
 
 
 
________________________________________________________________  
Subject Name 
 
 
__________________ 
 
 
____________          _______________ 
Witness Signature  
 
 
Date  
            Name 
 
 
___________________ 
 
 
____________          _______________ 
Physician Signature  
 
  
Date