| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus in Patients who have not Achieved Adequate Glycemic Control with Maximum Tolerated Dose of Metformin Daily or Sulfonylurea |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the change from Baseline in Glycated hemoglobin (HbA1c) up to Week 24 between 5 aminolevulinic acid/sodium ferrous citrate (5 ALA/SFC) plus metformin (or sulfonylurea [SU]) and placebo plus metformin (or SU). |
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| E.2.2 | Secondary objectives of the trial |
•To compare the occurrence of hypoglycemic episodes during the Treatment period between the 2-treatment arms
•To compare the change from Baseline in total body weight at Week 24 between the 2 arms
•To evaluate fructosamine as an alternative biomarker for glycemic control
•To explore glucose patterns of 5-ALA/SFC over the 24-hour period during 7 days at Baseline, Week 12 and Week 24, as captured through continuous glucose monitoring for the 2 arms
•To compare the need for rescue therapy of 5ALA/SFC plus metformin or SU with placebo plus metformin or SU
•To compare additional effects of 5-ALA/SFC plus metformin or SU with placebo plus metformin or SU at Week 24
•To explore the change from Baseline in laboratory assessments (hemoglobin, total bilirubin, and serum iron/ ferritin/unsaturated iron binding capacity/total iron binding capacity)
•To evaluate safety and tolerability of 5-ALA/SFC (adverse events, safety laboratory tests, Self-monitoring of blood glucose and ECG)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female between 18 and 75 years old (age >18 to ≤75) at time of informed consent, with a documented diagnosis of T2DM.
2.Written and signed informed consent needs to be provided by patients who are legally capable before starting any protocol-specific procedures.
3.HbA1c between 6.5% and 9% (both inclusive) based on central laboratory results from Visit 1, with individual need for therapy escalation (not to be re-assessed at Randomization Visit 3).
4.Currently treated with a stable MTD of metformin (immediate-release and extended-release) therapy ≥1500 mg/day or a SU for at least 12 weeks prior to enrolment visit. The patient should remain on therapy with metformin or SU will remain on the same dose for the duration of the study for both treatment arms indicated.
5.Patients willing to follow the CGM procedures.
6.BMI of ≤40 kg/m2 at Visit 1.
7.C-peptide laboratory value of ≥1.5 ng/mL (0.495 nmol/L) based on central laboratory results from Visit 1.
8.Female patients of childbearing potential who are sexually active who agree to routinely use adequate contraception from Screening throughout the duration of the study.
Women must be one of the following:
a.Naturally postmenopausal defined as ≥1 year without menstruation and ≥55 years, or
b.<55 years with follicle-stimulating hormone (FSH) ≥40.0 IU/L, or
c.Surgically sterile including hysterectomy, bilateral oophorectomy, and/or tubal ligation, or
d.Women of childbearing potential willing to use an highly effective method of contraception during the study and for 30 days after the EoT including:
i.oral birth control medications,
ii.placement of an intrauterine device with or without hormones,
iii.vasectomized male partner who is the sole partner for this patient.
9.Male patients must be using 2 acceptable methods of contraception one of which must be a physical barrier method, (eg, spermicidal gel plus condom; condom plus partner is sterilized at least 6 months prior) for the entire study duration and for at least 10 days following the last study medication/placebo administration.
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| E.4 | Principal exclusion criteria |
1.Any known complication of T2DM indicating a late disease state
2.History of Type 1 diabetes, maturity onset diabetes of the young, secondary DM or known presence of glutamate decarboxylase 65 antibodies
3.History of diabetic ketoacidosis, hyperosmolar non-ketotic coma, in the 6 months prior to Screening (Visit 1)
4.History of photo-hypersensitivity, porphyria, or hemochromatosis
5.Greater than 5% unexplained weight change during the 3 months prior to enrollment
6.Fasting plasma glucose >270 mg/dL (>15 mmol/L) assessed based on central laboratory results from Visit 1 (can be repeated once during the Screening period)
7.Patients who take acetaminophen containing medications on a regular basis and are unable/unwilling to substitute it the day before placement of the sensor and throughout the 7-day CGM periods
8.History of bariatric surgery or lap-band surgery, or either procedure planned during the time period of the study. History of liposuction is allowed
9.Patients with history of hypersensitivity to porphyrins or history of acute or chronic porphyria
10.History of any unstable endocrine, psychiatric, rapidly progressing or unstable renal disease, or rheumatic disorder
11.Patients who may be at risk for dehydration or volume depletion
12.Has evidence of current abuse of drugs or alcohol or a history of abuse within the past 52 weeks
13.Clinically significant cardiovascular disease or procedure within 3 months prior to enrollment
14.Severe uncontrolled arterial hypertension defined as systolic BP ≥180 mmHg and/or diastolic BP ≥110 mmHg at any visit up to and including the Randomization visit
15.Presence or history of severe congestive heart failure (Class III and IV)
16.Renal dysfunction with creatinine clearance <60 mL/min based on central laboratory results from Visit 1, or a diagnosed with nephrotic syndrome
17.Familial renal glucosuria
18.Significant hepatic disease, including, but not limited to, severe hepatic insufficiency and/or significant abnormal liver function defined as AST and/or ALT of >3 × upper limit of normal based on central laboratory results from Visit 1
19.Serum total bilirubin of >2.4 mg/dL (˃41 mmol/L) (patients with documented Gilbert’s syndrome will be allowed to enroll) based on central laboratory results from Visit 1
20.History of severe hepatobiliary disease or hepatotoxicity with any medication
21.History or serologic evidence of infectious liver disease including patients positive for Hepatitis B, C and HIV.
22.Any history within 5 years of Visit 1 (enrollment) of any malignancy, with the exception of treated in situ basal cell or squamous cell carcinoma of the skin
23.Hemoglobin <10 g/dL (<100 g/L) or 6.2 mmol/L for men; Hb <9.0 g/dL (<90 g/L) or 5.9 mmol/L for women
24.History of chronic hemolytic anemia or hemoglobinopathies
25.Donation or transfusion of blood, plasma, or platelets within the past 12 weeks prior to enrollment, or planning to donate blood during the study
26.In need of insulin treatment or having received insulin within 12 weeks before enrollment (Visit 1 )with the exception of short-term, acute insulin use for a period less than 7 days total
27.Administration of any anti hyperglycemic therapy, other than metformin or SU, during the 12 weeks prior to Visit 1 (enrollment). Exception for short-term insulin use (˂7 days total) during the 9 weeks prior to Visit 1.
28.Administration of any other investigational product or participation in any interventional clinical studies 30 days prior to Visit 1 (enrollment) or 5 half-lives, whichever is longer
29.Treatment with systemic glucocorticoids equivalent to oral prednisolone ≥10 mg per day for >7 days within 30 days prior to enrollment
30.Prescription or over-the-counter weight loss medications within 3 months prior to Visit 1 (enrollment)
31.Patient is pregnant, intends to become pregnant during the study or is lactating or gets pregnant within 30 days after study completion or last dose of study treatment
32.Clinically significant medical condition
33.Clinically significant abnormality identified on physical examination, ECG, or laboratory tests at Visit 1
34.Serum Zinc level for female: ≤0.59 µg/ml, male: ≤0.61 µg/ml assessed based on central laboratory results at Screening period.
35.Known contraindications, allergies, or hypersensitivities to any study medication or excipient as outlined in the IBs or local package inserts for metformin and SU.
36.Known immunocompromised status, including patients who underwent organ transplantation
37.Involvement in the planning and/or conduct of the study
38.Patients with presumable hypoxemia
39.Previous enrolment, and Randomization in the present study
40.Patients who may not be able to understand and/or comply with the study procedures
41.Hypersensitivity to iron present in the study medication. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change from Baseline in HbA1c to Week 24. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This endpoint will be evaluated at sreening, at baseline (Week 0), Week 4, 8, 12, 20 and Week 24. |
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| E.5.2 | Secondary end point(s) |
•Slope of change from Baseline in HbA1c from Baseline to Week 24.
•Achieving target HbA1c of 6.5% without significant hypoglycemia.
•Occurrence of least 1 episode of documented, symptomatic hypoglycemia during the 24 weeks Treatment period.
•Occurrence of at least 1 severe hypoglycemic event (2017 American Diabetes Association [ADA] classification) during the 24 weeks Treatment period.
•Occurrence of at least 1 episode of documented, symptomatic hypoglycemia during the 24 weeks Treatment period, in the age groups below 65 years and 65 years and older (18 to 64 years; 65 to 75 years).
•Achieving HbA1c of ≤7% and ≤6.5% without documented, symptomatic hypoglycemia at Week 24.
•Achieving HbA1c of ≤7% and ≤6.5% at Week 24.
•Achieving an HbA1c decrease of ≥1% with no weight gain at Week 24.
•Time spent at or below HbA1c target (≤7% and ≤6.5%) during the 24-weeks Treatment period.
•Change in fructosamine levels between Baseline and Week 24.
•Change in fructosamine levels at 4/8 week intervals from Baseline until
end of study
•Change in Hb, total bilirubin, and serum ferritin over the 24 weeks Treatment period.
•Change in body mass index (BMI) from Baseline to Week 24.
•Change in waist circumference from Baseline to Week 24.
•Achieving weight reduction of ≥5% or weight gain of ≥5% from Baseline to Week 24.
•Change in BP from Baseline to Week 24.
•Requiring rescue therapy for lack of glycemic control in the 2- treatment arms.
•Change in average CGM-measured blood glucose (CGMG) from Baseline to Week 12 and Week 24.
•Percent (%) of time in different CGM glucose ranges.
•Further CGM parameters (Area under curve [AUC], variability parameters).
Safety endpoints:
•Proportion of patients withdrawing from study due to hypoglycemia.
•AEs/ serious adverse events (SAEs).
•Adverse event of special interest.
•Clinical laboratory tests.
•ECG.
•Vital signs (pulse and BP).
•Body temperature.
•Hypoglycemic events.
•SMGB.
•Physical examinations.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical and safety measures will be assessed from Baseline up to Week
24. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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