Clinical trial NCT04854512: Investigational Study of Delayed Release Metformin
Official title: Randomized, Multicenter, Double-blind, Parallel-Group, Placebo & Comparator-Controlled Study to Compare the Glycemic Effects, Safety & Tolerability of Metformin Delayed-Release Tablets in Patients With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Anji Pharma
Sponsor class: INDUSTRY
First posted: 2021-04-22
Enrollment: 675
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In Phase 1 and 2 studies already conducted, Metformin DR, with its targeted delivery to the distal small intestine, has shown the potential to be a safe and effective way to improve glycemic control in patients with T2DM and CKD with less systemic metformin exposure. The primary purpose of this Phase 3 clinical study is to collect pivotal data confirming the safety and efficacy of Metformin DR in T2DM patients with varying renal function from normal up to CKD3B.

Detailed description: The study is a multicenter, international study with a 28 week randomized, double blind parallel group, placebo and active comparator controlled period and a 24 week open label extension period in patients with T2DM who are treated with metformin at the time of study screening.

Approximately 675 patients will be randomly assigned to 1 of 3 treatment groups. The study will assess change in HbA1c through 28 weeks for Metformin DR compared to placebo as a primary endpoint. In addition, assessments of change in HbA1c for Metformin DR compared to Metformin IR and assessment of absolute change in HbA1c will be evaluated in the study.

Screening and Run-in Period:

The study will include an up to 10-day screening period, an 4 to 8-week metformin washout period, and a 2-week single blind (patient blinded) placebo run-in period.

Treatment Period:

Patients that are determined eligible based upon the screening and run-in criteria will enter the 28-week double-blind treatment period. During the double-blind treatment period, patients will be randomly assigned to 1 of 3 treatment groups (Group A, B, or C) in a 1:1:1 ratio. The 3 treatments are Metformin DR (1800 mg Metformin DR with matching placebo for Metformin IR), Metformin IR (1500 mg Metformin IR with matching placebo for Metformin DR), and placebo (matching placebo for Metformin IR with matching placebo for Metformin DR). For those patients randomized to Metformin IR, their Metformin IR dose will be titrated to prevent gastrointestinal intolerability:

Open Label Extension Period:

Upon completion of the 28 week treatment patients will be eligible for an additional 24 weeks of open label extension period where assigned study treatment will continue and additional efficacy, safety and tolerability data will be collected and analyzed.

Eligibility criteria: Inclusion Criteria:

1. Is male or female and at least 18 years old
2. Has body mass index 20.0 to 45.0 kg/m2 (inclusive)
3. Has T2DM
4. Has HbA1c of 7.0% to 9.5%, inclusive, at Visit 1A and HbA1c value of 7.0% to 10.5%, inclusive, at Week -2 (Visit 3/3A as applicable)
5. Has an eGFR value of ≥30 mL/min/1.73 m2 based on the CKD-EPI equation at Visit 1A and Visit 3/3A (Week -2)
6. Stable treatment with a metformin preparation or a combination product containing metformin for 8 weeks prior to Visit 1A
7. If treated with the following medications, must be on a stable regimen for a minimum of 6 weeks prior to Visit 1B

   1. Drugs known to affect body weight, including prescription medications (e.g., phentermine, phentermine/topiramate, orlistat, lorcaserin, bupropion/naltrexone) and over-the-counter anti-obesity agents
   2. Hormone replacement therapy (female patients) and testosterone (male patients)
   3. Oral contraceptives (female patients)
   4. Antihypertensive agents including ACEi/ARB
   5. Lipid-lowering agents
   6. Thyroid replacement therapy
   7. Antidepressant agents
8. Ability to understand and willingness to adhere to protocol requirements

Exclusion Criteria:

1. Is currently on dialysis, has been on any dialysis within 1 year of Visit 1B, or is expected to undergo dialysis during the study period
2. Has a history of lactic acidosis
3. Has a fasting plasma glucose (FPG) value \>240 mg/dL (\>13.3 mmol/L) at Week -2 (Visit 3/3A as applicable)
4. An alanine aminotransferase or aspartate aminotransferase result \>2.5 × upper limit of normal (ULN) or a bilirubin result \>1.5 × ULN at Visit 1B or Visit 3/3A (Week -2) (except in case of documented Gilbert's syndrome)
5. Has a fasting plasma lactate value \>2 mol at Visit 1B
6. Has a bicarbonate value ≤20 mEq/L at both Visit 1A and 1B. If bicarbonate value is \<20 at Visit 3/3A or 4, patient may be excluded if the investigator considers this clinically significant
7. A history of \>5% weight change within 12 weeks prior to Visit 1A
8. Has mean BP measurements \>180 mmHg (systolic BP) or \>100 mmHg (diastolic BP) at Visit 1A or Visit 3/3A, which can be rechecked within 1 week (Note: re-screening is allowed 6 weeks after initiation/modification of antihypertensive agents if the patient is screen failed due to BP only)
9. Oral antidiabetic agent or insulin use that is not stable for 8 weeks prior to randomization (i.e., change in oral medication dose or basal insulin dose increased or decreased by more than 20% during the 8 weeks prior to Visit 4 \[Day 1\])
10. Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following excluded medications:

    1. Prescribed metformin preparation after initiation of metformin washout following Visit 1B
    2. Greater than 10 consecutive days of systemic corticosteroids by oral, intravenous, or intramuscular route within 12 weeks of Visit 1B; inhaled, intranasal, ophthalmic, topical, or intra-articular corticosteroids are not exclusionary
    3. Planned use of proton pump inhibitors after Visit 2 (Week -6); such use could potentially affect the DR and PK of Metformin DR. Proton pump inhibitor treatment may be replaced by other treatment (such as H2 receptor antagonists \[excluding ranitidine\], or calcium carbonate antacids) prior to Visit 4 (Day 1), if appropriate per the judgment of the Investigator
    4. Cationic drugs that are eliminated by renal tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, flecainide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) within 1 week of Visit 3 (Week 2)
    5. Iodinated contrast dye within 1 week prior to Visit 3 (Week -2)
    6. Investigational drug within 8 weeks (or 5 half-lives of the investigational drug, whichever is greater) of the date of the first dose of randomized study medication
    7. Metformin DR or double-blind matching placebo for Metformin DR at any time prior to Visit 1B
11. Has a clinically significant medical condition as judged by the Investigator that could potentially affect study participation and/or personal well-being, including but not limited to the following conditions:

    1. Hepatic disease
    2. Gastrointestinal disease, including but not limited to:

    i. History or presence of inflammatory bowel disease or other severe gastrointestinal disease, particularly those that may impact gastric emptying, such as gastroparesis and pyloric stenosis ii. Prior or expected surgical gastrointestinal procedure that may impact the gut hormonal response to study medication such as gastric bypass surgery or gastric banding surgery iii. Active diagnosis of pancreatitis c. Endocrine disorder other than T2DM or hypothyroidism on replacement therapy d. Cardiovascular disease, including history of stroke, decompensated heart failure New York Heart Association Class III or IV, myocardial infarction, unstable angina pectoris, or coronary arterial bypass graft or angioplasty within 3 months prior to Visit 1A (screening) e. Central nervous system diseases such as epilepsy f. Psychiatric or neurological disorders that in the Investigator's opinion would cause the patient to be noncompliant with study procedures g. Organ transplantation h. Chronic or acute infection requiring systemic antibiotic treatment i. Orthostatic hypotension or syncope j. Active malignancy within the past 5 years with exception of basal cell and squamous cell carcinoma
12. Known allergy or hypersensitivity to Metformin DR, Metformin IR, or placebo or any inactive component of study medication, active comparator, or placebo, unless the reaction is deemed irrelevant to the study by the Investigator (prior history of gastrointestinal intolerance to metformin is not exclusionary)
13. Has a history of diabetic ketoacidosis or hyperosmolar non-ketotic hyperglycemia within 1 year prior to Visit 1B
14. A physical, psychological, or historical finding that, in the Investigator's opinion, would make the patient unsuitable for the study
15. Any verified clinically significant abnormality identified on physical examination, laboratory tests, ECG, vital signs, or any adverse event (AE) at the time of Visit 1B through Visit 4 that, in the judgment of the Investigator or any Sub-investigator, would preclude safe completion of the study or constrains efficacy assessment
16. Currently abuses drugs or alcohol or has a known history of abuse that in the Investigator's opinion would cause the patient to be noncompliant with study procedures
17. Had a blood transfusion or experienced significant blood loss (i.e., \>500 mL), including loss due to blood donation, within 8 weeks prior to Visit 1B, or is planning to donate blood or have a blood transfusion during the study
18. Prior or planned major surgery of any kind (requiring overnight hospitalization) within 6 months of Visit 1B
19. Patients insufficiently compliant with study medication during the placebo run-in phase (\<85% or \>115%) as assessed at Visit 4
20. Is screening for the study at more than one clinical site or is participating in any other clinical study
21. Is currently pregnant (confirmed by serum pregnancy test at Visit 1B) or breastfeeding or plans to become pregnant during the course of the study
22. Women of childbearing potential not willing to use highly effective method(s) of birth control during the entire study, or who are unwilling or unable to be tested for pregnancy
23. If the patient has evidence of coronavirus disease 2019 (COVID-19) within 2 weeks prior to enrolment (a positive COVID-19 test or suspicion of COVID-19 infection), the patient cannot be enrolled in the study
24. Is employed by Anji Pharma (that is an employee, contract worker, or designee of the company).

Primary outcomes:
measure: Change in HbA1c
timeFrame: Baseline to 28 weeks
Secondary outcomes:
measure: HbA1c response (Metformin DR vs. placebo)
timeFrame: Baseline to 28 weeks
measure: Change in HbA1c (Met DR vs. metformin IR)
timeFrame: Baseline to 28 weeks
measure: HbA1c response (Metformin DR vs. metformin IR)
timeFrame: Baseline to 28 weeks
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Lenzmeier Family Medicine/CCT Research
state: Arizona
city: Mesa
country: United States
facility: Aventiv Research
state: Arizona
city: Apple Valley
country: United States
facility: Kidney & Hypertension Center / DaVita Clinical Research
state: California
city: Chula Vista
country: United States
facility: California Institute of Renal Research
state: California
city: Los Angeles
country: United States
facility: Academic Medical Research Institute
state: California
city: Northridge
country: United States
facility: Valley Renal Medical Group Research
state: California
city: Van Nuys
country: United States
facility: San Fernando Valley Health Institute
state: California
city: Hialeah
country: United States
facility: AGA Clinical Trials
state: Florida
city: Jacksonville
country: United States
facility: East Coast Institutue for Research
state: Florida
city: Lake City
country: United States
facility: East Coast Institute for Research, LLC
state: Florida
city: Ocoee
country: United States
facility: West Orange Endocrinology
state: Florida
city: West Palm Beach
country: United States
facility: Metabolic Research Institute, Inc
state: Florida
city: Lawrenceville
country: United States
facility: Georgia Nephrology Research Institute
state: Georgia
city: Peachtree Corners
country: United States
facility: In-Quest Medical Research - Peachtree
state: Georgia
city: Louisville
country: United States
facility: Louisville Metabolic and Atherosclerosis Research Center Inc. (L-MARC)
state: Kentucky
city: Fremont
country: United States
facility: Methodist Physicians Clinic / CCT Research
state: Nebraska
city: Omaha
country: United States
facility: Midwest Regional Health Services
state: Nebraska
city: Las Vegas
country: United States
facility: DaVita Clinical Research
state: Nevada
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Albuquerque
country: United States
facility: Albuquerque Clinical Trials, Inc.
state: New Mexico
city: Fayetteville
country: United States
facility: Carolina Institute for Clinical Research
state: North Carolina
city: Morehead City
country: United States
facility: Lucas Research
state: North Carolina
city: New Bern
country: United States
facility: Eastern Nephrology Associates
state: North Carolina
city: Myrtle Beach
country: United States
facility: Family Medicine of SayeBrook
state: South Carolina
city: Orangeburg
country: United States
facility: South Carolina Clinical Research LLC
state: South Carolina
city: Chattanooga
country: United States
facility: WR-ClinSearch
state: Tennessee
city: Austin
country: United States
facility: Texas Diabetes & Endocrinology
state: Texas
city: Corpus Christi
country: United States
facility: Office of Osvaldo A Brusco, MD
state: Texas
city: Dallas
country: United States
facility: Galenos Research
state: Texas
city: Houston
country: United States
facility: Endocrine IPS, PLLC
state: Texas
city: San Antonio
country: United States
facility: Clinical Advancement Center, PLLC
state: Texas
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: Suffolk
country: United States
facility: IACT Health
state: Virginia
city: Fortaleza
country: Brazil
facility: Instituto de Ensino e Pesquisa Clinica do Ceara
state: CE
city: Fortaleza
country: Brazil
facility: Centro de Pesquisas em Diabetes e Doencas Endrocrino-Metabolica Ltda
state: CE
city: Belem
country: Brazil
facility: Universidade Federal Do Para (UFPA) - Insitituto de Ciencas de Saude (ICS)
state: PA
city: Curitiba
country: Brazil
facility: Centro de Diabetes Curitiba
state: PR
city: Curitiba
country: Brazil
facility: Cline Research Center
state: PR
city: Rio De Janeiro
country: Brazil
facility: IBPClin Instituto Brasil de Pesquisa Clinica
state: RJ
city: Passo Fundo
country: Brazil
facility: Hospital Sao Vicente de Paulo
state: RS
city: Porto Alegre
country: Brazil
facility: Centro de Pesquisas em Diabetes Ltda
state: RS
city: Campinas
country: Brazil
facility: Loema - Instituto de Pesquisa Clinica
state: SP
city: Campinas
country: Brazil
facility: Instituto de Pesquisa Clinica de Campinas
state: SP
city: Ruse
country: Bulgaria
facility: ASOMC Endocrinology and Metabolic Diseases
city: Ruse
country: Bulgaria
facility: Medical Cetner Teodora
city: Smolyan
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment
city: Sofia
country: Bulgaria
facility: Fourth Multipfoile Hospital for Active Treatment
city: Stara Zagora
country: Bulgaria
facility: Medical Center New Rehabilition Cetner EOOD
city: Varna
country: Bulgaria
facility: Diagnostic Culsultative Cetner "Equita" EOOD
city: Varna
country: Bulgaria
facility: Medical Center Leo Clinical EOOD
city: Vancouver
country: Canada
facility: BC Diabetes
state: British Columbia
city: Barrie
country: Canada
facility: LMC Manna Research (Barrie)
state: Ontario
city: Brampton
country: Canada
facility: LMC Manna Research (Brampton)
state: Ontario
city: East York
country: Canada
facility: Stephen S. Chow Medicine Professional Corporation
state: Ontario
city: Etobicoke
country: Canada
facility: LMC Manna Research (Etobicoke)
state: Ontario
city: Nepean
country: Canada
facility: LMC Manna Research (Ottawa)
state: Ontario
city: Toronto
country: Canada
facility: LMC Manna Research (Bayview)
state: Ontario
city: Montreal
country: Canada
facility: LMC Manna Research (Montreal)
state: Quebec
city: Holešov
country: Czechia
facility: Diahaza s.r.o.
city: Krnov
country: Czechia
facility: Diabetologicka ambulance
city: Olomouc
country: Czechia
facility: Interni Ambulance
city: Praha
country: Czechia
facility: Endodiab s.r.o.
city: Praha
country: Czechia
facility: Diabet2 s.r.o.
city: Praha
country: Czechia
facility: Diabetologicka a podiatricka ambulance, Milan Kvapil s.r.o.
city: Praha
country: Czechia
facility: ResTrial s.r.o.
city: Nyiregyhaza
country: Hungary
facility: Borbanya Praxis EU Kft
state: SZ
city: Baja
country: Hungary
facility: Lausmed Kft
city: Baja
country: Hungary
facility: Principal SMO Ltd
city: Balatonfüred
country: Hungary
facility: DRC Gyogyszervizsgalo Kozpont Kft
city: Budapest
country: Hungary
facility: Bajscy-Zsilinszky Hospital
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyl Koxpont
city: Debrecen
country: Hungary
facility: Borbanya Praxis EU k ft
city: Zalaegerszeg
country: Hungary
facility: Zala Megyei Szent Rafael Korhaz
city: Lublin
country: Poland
facility: NZOZ NEUROMED M.iM. Nastaj Sp.P.
state: LU
city: Kraków
country: Poland
facility: Malopolskie Centrum Kliniczne
state: MA
city: Białystok
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej Specjalistyczny Ośrodek Internistyczno-Diabetologiczny
city: Katowice
country: Poland
facility: Centrum Medyczne Pratia
city: Katowice
country: Poland
facility: Pro Familia Altera Sp. z.o.o.
city: Krakow
country: Poland
facility: Diamond Medical Center
city: Warsaw
country: Poland
facility: NBR Polska
city: Warsaw
country: Poland
facility: Centralny Szpital Kliniczny Ministerstwa Spraw Wewnetrznych i Administracji
city: Wrocław
country: Poland
facility: Centrum Badan Klinicznych Piotr Napora Lekarze Spolka Partnerska, Centrum Badan Klinicznych Osrodek Badan Wczesnej Fazy
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
state: SE
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Nuevas Tecnologias en Diabetes y Endocrinologia
city: Sevilla
country: Spain
facility: Hospital Vithas Sevilla
Study officials:
affiliation: Chief Medical Officer - Anji Pharma
name: Dan Meyers, MD
role: STUDY_CHAIR
References: