The purpose of this study is to investigate how quickly and to what extent branaplam is absorbed and eliminated from the body (this is called pharmacokinetics). Branaplam will be labelled with Carbon-14 (14C) and is thus radioactive. In this way…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To characterize the plasma pharmacokinetics (PK) of branaplam and its
metabolite UFB112.
- To determine the PK of total radiolabeled components in blood and plasma.
- To determine the rates and routes of excretion of total radiolabeled
components, including mass balance of total radiolabeled components in urine
and feces following a single 140-mg dose of [14C]branaplam in healthy male
participants.
Secondary outcome
To assess the safety and tolerability of a single 140-mg oral dose of
[14C]branaplam administered to healthy male participants.
Background summary
Branaplam is a new compound that may potentially be used for the treatment of
the muscle disease spinal muscular atrophy (SMA) and Huntington*s disease.
With SMA, a certain substance (SMN protein) is not produced properly. This
protein is important for the survival of the nerve cells that control muscles.
The symptoms of this disease often appear at a young age, and in the most
severe form of this disease, children often die before they are 2 years old.
Branaplam ensures that the SMN protein is properly produced, so that these
nerve cells continue to live and the muscles continue to work.
In Huntington's disease, the substance HTT (huntingtin protein) is produced
incorrectly. This causes nerve cells to malfunction and eventually die.
Huntington's disease symptoms usually start between the age of 30 and 50. In
this disease, the functioning of the muscles and mental faculties are affected,
and also psychiatric symptoms develop. These worsen the longer the disease
lasts. Branaplam prevents the production of this faulty HTT protein, and it is
expected to slow down the course of the disease.
Study objective
The purpose of this study is to investigate how quickly and to what extent
branaplam is absorbed and eliminated from the body (this is called
pharmacokinetics). Branaplam will be labelled with Carbon-14 (14C) and is thus
radioactive. In this way branaplam can be traced in blood, urine and feces.
It will also be investigated how safe the new compound branaplam is and how
well it is tolerated when it is administered to healthy volunteers. Branaplam
has been administered to humans before. It has also been previously tested in
the laboratory and on animals.
Study design
The actual study will consist of 1 period during which the volunteer will stay
in the research center for 23 days (22 nights).
Day 1 is the day of administration of the study treatment. The volunteer is
expected at the research center at 12:00 h in the afternoon 2 days prior to the
day of administration of the study treatment, so on Day -2.
The volunteers participation in the entire study, from the screening until the
last follow-up visit, will depend on the amount of radioactivity left in urine
and feces at the end of the study (Day 21). The amount of radioactivity in
urine and feces will be measured daily from Day 1 onwards. The volunteer should
be aware that if the radioactivity levels are still above the pre-defined
levels on Day 21, he will need to return to the research center for up to 4
additional 24-hour visits for the collection of urine, feces and blood. The
volunteer will be contacted by phone as soon as possible and be told if he has
to come back for the 24-hour visits or not.
For the additional 24-hour visits, the volunteers are expected at the research
center at 11:00 h in the morning of Day 27, 34, 41, and 48. The volunteer will
leave the research center on Days 28, 35, 42 and 49, respectively. During his
stay, his urine and feces will be collected, and his blood will be sampled each
day to measure the amount of radioactivity. Depending on the test results of
the amount of radioactivity left in his blood, urine and/or feces, 24-hour
visits can be cancelled.
The volunteer will once receive 140 milligram (mg) 14C-labeled branaplam as an
oral solution of 40 milliliters (mL). Thereafter he is are also required to
drink an additional amount of 240 mL of water. This amount contains 0.74 MBq
(20 µCi) radioactivity.
Intervention
Day -2 Entry into the research center
Day Administration of [14C]branablam
Day 2-21 Washout
Day 21 The volunteer will leave the research center
Day 27-28 (1) 24-hour visit
Day 34-35 (1) 24-hour visit
Day 41-42 (1) 24-hour visit
Day 48-49 (1) 24-hour visit
5 to 10 days after the volunteer leaves the clinic, or after the last visit
Follow-up
(1.) Depending on the volunteers radioactivity levels, these visits can be
cancelled.
Study burden and risks
Possible side effects and discomforts
In 1 ongoing study, a total of 38 children with SMA have been treated with
branaplam so far. In another ongoing study in healthy adult volunteers, 24
persons have received branaplam in doses of 35 mg, 105 and 210 mg.
In general, branaplam was well tolerated in SMA patients treated during 13
weeks or 52 weeks. The side effects that were most often observed were fever,
pneumonia, vomiting, diarrhea, upper respiratory tract infection,
thrombocytosis (increase in the platelets in blood, platelets are blood cells
from clots to stop bleeding), decrease in blood creatinine levels (low
creatinine levels can indicate a lower muscle mass), constipation and stuffy
and runny nose (rhinitis).
These side effects were observed in young patients who were treated for weeks.
During this study the volunteer will only receive single dose, therefore the
chance is small that he will experience these side effects.
Branaplam, in single doses up to 210 mg was well tolerated in healthy
volunteers. Five out of 24 volunteers experienced side effect. The most common
side effects observed until now are inflammation of the eyelids, back pain,
diarrhea and flu-like symptoms. All these side effects were mild and were
likely not caused by branaplam.
In animals (dogs and monkeys) that were treated multiple times with branaplam,
increases in the biomarker NfL (neurofilament light chain) were seen in blood
and the brain. This NfL can be a marker for damage to brain cells. In dogs some
damage was observed after 17 weeks of treatment with branaplam. But in monkeys,
which were treated for 6 weeks, no damage was observed. In the first study in
healthy adult volunteers, that is currently ongoing, NfL is being measured in
blood samples. Up to date, no changes herein were observed after single
administration of 35, 105 or 210 mg branaplam.
The study compound may also have side effects that are still unknown.
Possible discomforts due to procedures
Drawing blood and/or insertion of the indwelling cannula (tube in an arm vein)
may be painful or cause some bruising.
In total, we will take no more than 500 milliliters (mL) of blood from the
volunteer. This amount does not cause any problems in adults. To compare: a
blood donation involves 500 mL of blood being taken each time.
To make a heart tracing, electrodes (small, plastic patches) will be pasted at
specific locations on the volunteers arms, chest and legs. Prolonged use of
these electrodes can cause skin irritation (rash and itching).
Samples for the coronavirus test will be taken from the back of the volunteers
nose and throat using swabs. Taking the samples only takes a few seconds, but
can cause discomfort and can give an unpleasant feeling. Taking a sample from
the back of the volunteers throat may cause him to gag. When the sample is
taken from the back of the volunteers nose, he may experience a stinging
sensation and his eyes may become watery.
Exposure to radiation
This study involves using radioactive markers. The additional amount of
radiation the volunteer will be exposed to in this study is 1.98 mSv. To
compare: the background radiation in the Netherlands is ~2.5 mSv per year. The
additional radiation you will be exposed to in this study is thus ~82% compared
to the average yearly annual radiation burden. This amount of radioactivity is
seen as both the minimum needed for the study and the maximum acceptable from a
radiation dose point of view.
Lichtstrasse 35
Basel CH-4056
CH
Lichtstrasse 35
Basel CH-4056
CH
Listed location countries
Age
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study.
2. Healthy male participants age 30 to 54 years, both inclusive.
3. In good health as determined by medical history, physical examination, vital
signs, ECG, and laboratory tests at screening.
4. Laboratory values within the reference range at the local laboratory, unless
deemed not clinically significant by the investigator or designee.
5. Sexually active male participants must agree to use a condom during
intercourse for the entire study duration and for up to 90 days after dosing,
and should not father a child in this period. A condom is required to be used
also by vasectomized men to prevent delivery of the drug via seminal fluid.
For complete overview see the protocol
Exclusion criteria
1. Use of other investigational drugs within 5 half-lives of initiation of
study treatment (if known), or within 6 months prior to admission (in case of
therapeutics with expected long half-lives such as immunoglobulin [Ig]G
antibodies), or within 30 days after dosing (for small-molecule drugs with
daily dosing scheme), or longer if required by local regulations.
The investigator is expected to apply the appropriate due diligence
(considering available information in public, IBs, and/or patient information)
to ensure that the washout times detailed above are sufficient to avoid a
carry-over of PK or PD or have an impact on participant safety by the other
investigational drug.
2. Evidence of any remaining PD effects not having yet returned to baseline
after previous exposure to an investigational drug (in the judgment of the
investigator).
3. Absence of regular defecation pattern (participants with a mean defecation
frequency of less than on average once per 2 days or chronic diarrhea).
4. Any surgical or medical condition that might significantly alter the ADME of
drugs, or which may jeopardize the participant in case of participation in the
study. The investigator should make this determination in consideration of the
participant*s medical history and/or clinical or laboratory evidence of any of
the following at screening or baseline:
• Inflammatory bowel disease, peptic ulcers, GI including rectal bleeding.
• Major GI tract surgery such as gastrectomy, gastroenterostomy, or bowel
resection.
• Pancreatic injury or pancreatitis.
• Liver disease or liver injury as indicated by abnormal liver function tests.
Alanine aminotransferase (ALT); serum glutamic pyruvic transaminase, aspartate
aminotransferase (AST); serum glutamic oxaloacetic transaminase, gamma-glutamyl
transferase (GGT); alkaline phosphatase (ALP); and serum bilirubin will be
tested.
• History or presence of impaired renal function as indicated by clinically
significantly abnormal creatinine or blood urea nitrogen (BUN) and/or urea
values, abnormal urinary constituents (e.g., albuminuria).
• Evidence of urinary obstruction or difficulty in voiding.
5. History of drug abuse or harmful alcohol use within the 12 months prior to
dosing, or evidence of such abuse as indicated by the laboratory assays
conducted during screening and baseline. Harmful alcohol use is defined as a
history of, or current alcohol misuse/abuse, defined as *exceeding 21
units/week (''units* generally contain between 8 and 14 grams of pure ethanol)."
For complete overview see the protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004239-22-NL |
| CCMO | NL75923.056.20 |