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

NCT05402891 | Completed Phase 2 DMC

• 1 other identifier: NL80308.018.22
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Familial Adenomatous Polyposis

Keywords

Familial Adenomatous Polyposis; Chemopreventive therapy; Adenoma development; Lithium carbonate

Outcome Measures

Primary Outcomes (1)

• Change in clone size distribution positive for NOTUM.

  For each patient crypts will be retrieved form normal tissue biopsies through colonoscopy. APC mutant stem cell dynamics will be determined by tracing the spread of the APC mutant cells using specific expression of NOTUM by RNAscope (in situ hybridization). 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) (12). This will result in an average clone size distribution for each patient per time point, as well as the proportion of fixed crypts. By analyzing the differences in clone size distribution before, during and after Lithiumcarbonate treatment we aim to observe a relative reduction in average clone size of 50% during the lithiumcarbonate treatment, as well as a reduction in crypt fixation of 50%.

  Month 0, Month 6, Month 12, Month 18

Secondary Outcomes (3)

• Change in number and size of polyps (defined as polyp burden)

  Month 0, Month 6, Month 12, Month 18

• Patient reported side effects of Lithiumcarbonate using a Lithium side effect questionnaire

  Month 0, Month 6 (day 22), Month 9

• Safety outcomes by analysing reported adverse events, physical examination and laboratory findings.

  Physical examination (including vital signs) at baseline and every six months (at time of endoscopy). Interviewing: month 0, month 3, month 6, month 7, month 9, month 11, month 12, month 15, month 18, month 19. Laboratory testing will be done at baseline

Other Outcomes (4)

• Number of cups of coffee per day (decaffeinated coffee not included)

  month 0, month 3, month 6, month 7, month 9, month 11, month 12, month 15, month 18

• Turmeric use (gram per day)

  month 0, month 3, month 6, month 7, month 9, month 11, month 12, month 15, month 18

• Number of fish oil capsules per day (amount of eicosapentaenoic acid in terms of mg)

  month 0, month 3, month 6, month 7, month 9, month 11, month 12, month 15, month 18

Study Arms (1)

Study population

EXPERIMENTAL

Every patient will receive treatment: Lithiumcarbonate 300mg daily in oral tablet for six months. There will no control group included since patient represent their own control in the nontreatment-phase.

Drug: Lithium Carbonate

Interventions

Lithium Carbonate DRUG

Patients will be administered lithiumcarbonate by an oral tablet of 300mg once a day for a duration of 6 months. Starting dose is 200mg for the first 5 days, dosage will be then increased to 300mg. To limit adverse events and side-effects, the lowest effective dose will be administered. The target serum level of lithium is 0.20 - 0.40 mmol/L and this will be maintained by regular lithium level testing.

Study population

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead

Study Sites (1)

Academic Medical Centre

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Related Publications (2)

• van 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 BACKGROUND

• Linssen 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 DERIVED

MeSH Terms

Conditions

Adenomatous Polyposis Coli

Interventions

Lithium Carbonate

Condition Hierarchy (Ancestors)

Adenomatous Polyps; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplastic Syndromes, Hereditary; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Polyposis; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Carbonates; Alkalies; Inorganic Chemicals; Carbonic Acid; Carbon Compounds, Inorganic; Lithium Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Professor

Model Details: A prospective phase II, single arm pilot trial, with a duration of 18 months. The drug will be administered between month 6 and 12. 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. The duration of this study will be 18 months, and patients will undergo four colonoscopies in total (at t=0, t=6, t=12, t=18). During each colonoscopy biopsies from normal intestinal mucosa will be collected to determine stem cell dynamics.

Study Record Dates

• First Submitted: May 25, 2022
• First Posted: June 2, 2022
• Study Start: June 2, 2022
• Primary Completion: September 30, 2024
• Study Completion: September 30, 2024
• Last Updated: October 4, 2024

Record last verified: 2024-10

Locations

NL (1)