The aim of this study is to investigate the effect of low-dose Lithium on stem cell dynamics, the number and size of polyps and, to assess safety outcomes of this drug in FAP patients.
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Clone sizes will be quantified as proportions of the crypt circumference
positive for NOTUM (in parts of eight, 1:8 to 8:8). When a whole crypt is
positive for NOTUM (8:8), this crypt is fixed (crypt fixation).
Secondary outcome
- Difference in number and size of polyps between baseline and end of study
- Patient reported side effects of Lithium using a Lithium side effect
questionnaire (see appendix 2 of the protocol)
- Safety outcomes by analysing reported adverse events, physical examination
and laboratory findings.
Background summary
Familial adenomatous polyposis (FAP) syndrome is characterized by the
development of numerous colorectal polyps. If left untreated, these patients
have a chance of nearly 100% of developing colorectal cancer (CRC) at a young
age. Therefore, guidelines recommend a prophylactic colectomy during early
adulthood. Even after colectomy, most patients will develop adenomas in the
retained rectum or ileoanal pouch requiring further endoscopic surveillance. In
a recent study in mouse models, a chemopreventive effect of Lithium was
observed on the spread of Apc mutated cells within the crypts of normal
intestinal mucosa, suggesting polyp formation can be prevented. Lithium is used
to treat patients with bipolar disorders but has never been investigated in
patients with FAP aiming to reduce polyp burden. We hypothesize that Lithium
could reduce the spread of APC mutated cells within the crypt of normal
intestinal mucosa potentially reducing polyp burden in patients with FAP.
Study objective
The aim of this study is to investigate the effect of low-dose Lithium on stem
cell dynamics, the number and size of polyps and, to assess safety outcomes of
this drug in FAP patients.
Study design
A prospective phase II, single arm pilot trial that will take place at the
Amsterdam Universitair Medisch Centrum (AMC), with a duration of 18 months. The
drug will be administered between month 6 and 12.
Intervention
All patients will be treated with Lithium with an oral dose of 300mg a day for
six months, achieving a therapeutic serum level between 0.2-0.4 mmol/L.
Study burden and risks
A physical examination and an endoscopy with biopsies will be performed at
baseline and every six months (four in total). Laboratory testing will be done
at baseline and every two months during Lithium treatment. Patients will be
interviewed by phone and Lithium side effect questionnaires will be obtained at
baseline and during Lithium treatment. Lithium serum levels will be measured at
day 12 and 22 after start of the study drug (at month 6). When the therapeutic
range has been achieved, serum level testing will be done every month. Most
relevant side-effects that could potential occur include polyuria,
hyperparathyroidism and hypothyroidism. Most side effects are dose-dependent
and will be regularly monitored. Patients with FAP could potentially benefit
from a chemopreventive therapy such as Lithium to postpone or even avoid
invasive types of surgery.
meibergdreef 9
Amsterdam 1105 AZ
NL
meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Male or female between the age of 18 and 35 years;
- Confirmed APC germline mutation;
- Positive family history of a classical FAP phenotype (>100 colorectal
adenomas);
- Intact colon, with a minimum of 50 polyps;
- Participant is willing and able to give informed consent for participation
Exclusion criteria
- Participation in any other clinical intervention study; observational trials
accepted;
- Lithium use prior to participation of the study;
- Pregnancy, breast-feeding or no use of anticonception;
- No normal intestinal mucosa left for normal tissue biopsy;
- Indication for colectomy within 2 years;
- Known renal impairment, defined as GFR < 60 ml/min;
- Known severe cardiac disorder;
- Known severe brain injury;
- Hypothyroidism;
- Hyponatremia, defined as Na < 130mmol/L;
- Positive family history of Brugada syndrome
- Co-medication known for interacting with Lithium (as defined in the protocol).
- Regular NSAID use (defined as more than twice a week for 4 consecutive weeks)
within 3 months prior to baseline;
- Use of immunosuppressive or anti-inflammatory drugs within 3 months prior to
baseline;
- Use of any other FAP directed drug therapy within 3 months prior to baseline
(use of any alternative supplements e.g. turmeric or fish-oil must be noted in
questionnaire).
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 | EUCTR2022-000240-30-NL |
| CCMO | NL80308.018.22 |