The CHAMP-study: The CHemopreventive Effect of Lithium in Familial AdenoMatous Polyposis

Rationale: 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. 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, with a duration of 18 months. The drug will be administered between month 6 and 12. Study population: Twelve patients with FAP between the age of 18 and 35 not having undergone a colectomy (yet), having a genetically confirmed APC mutation and a family history with a classical FAP phenotype. 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. Main study parameters/endpoints: The main outcome parameter is the effect of Lithium on the spread of APC mutant cells within intestinal crypts over time by using an APC specific marker NOTUM (a significance reduce of fixed crypts and reduction of fixed clone size of 50%). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: 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.

Sex

All

Minimum age

18 Years

Maximum age

35 Years

Inclusion Criteria:

Patients must meet all of the following criteria for inclusion in the study:

* Age between 18 and 35 years;
* Confirmed APC germline mutation and one of the following:

  * Minimum of 100 colorectal adenomas
  * Minimum of 50 colorectal adenomas and a positive family history of a classical FAP phenotype (\>100 colorectal adenomas);
* Intact colon;
* Participant is willing and able to give informed consent for participation.

Exclusion Criteria:

Patients that meets any of the following criteria will be excluded from participation in this study:

* 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
* 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).

• BACKGROUNDvan Neerven SM, de Groot NE, Nijman LE, Scicluna BP, van Driel MS, Lecca MC, Warmerdam DO, Kakkar V, Moreno LF, Vieira Braga FA, Sanches DR, Ramesh P, Ten Hoorn S, Aelvoet AS, van Boxel MF, Koens L, Krawczyk PM, Koster J, Dekker E, Medema JP, Winton DJ, Bijlsma MF, Morrissey E, Leveille N, Vermeulen L. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature. 2021 Jun;594(7863):436-441. doi: 10.1038/s41586-021-03558-4. Epub 2021 Jun 2. PMID 34079128
• DERIVEDLinssen JDG, van Neerven SM, Aelvoet AS, Elbers CC, Vermeulen L, Dekker E. The CHAMP-study: the CHemopreventive effect of lithium in familial AdenoMatous Polyposis; study protocol of a phase II trial. BMC Gastroenterol. 2022 Aug 12;22(1):383. doi: 10.1186/s12876-022-02442-3. PMID 35962368