Trial document




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  DRKS00003127

Trial Description

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Title

Oromucosal Delivery of Insulin: “Proof of Concept” Using a Mucoadhesive Wafer Dosage Form Containing Insulin.

A single-center study with two parts: Part 1 comparing lingual/palatal versus gingival insulin wafer administration according to an open-label, parallel-group design, and, on condition that satisfactory exposure has been achieved, Part 2 investigating positive and negative control according to a double blind, crossover design. PART 2

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

Diabetes mellitus (diabetes) is a condition characterized by chronically raised blood sugar levels. The high blood sugar level in patients with long-term diabetes mellitus leads to diseases that affect mainly the eyes, kidneys, nervous system, heart, brain, and blood vessels. Diabetes occurs because the person’s body has too little of the hormone insulin (Type 1 diabetes) or because the body has a problem responding to the insulin it produces (Type 2 diabetes). Insulin is a hormone made in the pancreas. Insulin regulates the blood sugar level - it tells the cells to take up glucose from the blood and in this way lowers the blood sugar level. For patients with diabetes it is very important to keep the level of blood sugar as close to normal as possible.
In the past, vial and syringe or insulin pens were the standard means of administering insulin to patients with diabetes mellitus. However, not all patients were comfortable with these methods and this has implications on the treatment schedule and blood sugar level. In the present study, insulin will reach the bloodstream by diffusion through the mucous membranes in the mouth (orosomucosal delivery). This is a new way to administer insulin, possibly sparing the patients syringes or Insulin pens. Oromucosal delivery is a simple and convenient method for drug administration even for people with visual impairment and /or dexterity problems facilitating improved patient compliance.
The aim of this study is to examine the pharmacokinetic (uptake, distribution, metabolism, and excretion) as well as pharmacodynamic (effect of a medication on the body) properties of insulin from the wafer formulation in healthy male subjects. To do this, blood samples will be collected during the study.
The insulin wafer tested in this study is a new way to administer insulin. The insulin wafer is a thin film which clings to the mucosa inside the mouth. Each insulin wafer contains 75 IU of insulin. Insulin from the wafer diffuses through the oral mucosa into the bloodstream. Two wafers will be used for each type of administration. One each will be applied either on the upper side of the tongue and under the hard palate (lingual/palatal administration) or on the upper gum and the lower gum (gingival administration). In this study a so-called placebo medication will also be used. These are wafers that do not contain any insulin.
In Part 1 of this study, a comparison will be made regarding the amount of insulin that enters the bloodstream after a single lingual/palatal administration and after gingival administration.
In Part 2 of this study, the same healthy subjects who have participated in Part 1 of the study will receive two placebo wafers together with a single subcutaneous (under the skin) injection of about 0.2 mL insulin solution (corresponding to 7.5 IU insulin) and, after a minimum washout period of 6 days, again two placebo wafers together with a single subcutaneous injection of about 0.2 mL physiological saline. Results from Part 2 will be compared with those from Part 1. Part 2 of the study will be performed only if satisfactory data are obtained in Part 1 (i.e. if sufficient amount of insulin has diffused from the insulin wafer into the blood stream).
Part 1 and Part 2 of the study will be separated by a washout period of at least 6 days. For each study participant the overall duration of Part 1 of the study, including the screening examination, is 22 days; for both periods of Part 2, including the post study examination, the duration is planned for 16 days. If only Part 1 of the study is performed, the duration is planned for 29 days which includes the post study examination.

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Brief Summary in Scientific Language

Diabetes mellitus is a metabolic disorder, characterized by chronic high blood glucose levels (hyperglycemia) with disturbances of carbohydrate, fat, and protein metabolism. Diabetes requires long-term medical therapy. The disease develops due to a diminished production of insulin (type 1 diabetes) or a decreased insulin activity or a combination of both factors (type 2 diabetes). Patients with type 1 diabetes mellitus require exogenous insulin therapy due to the little or no endogenous insulin secretory capacity. The early addition of insulin to oral therapy in patients with type 2 diabetes is recognized as an effective option that can help improve glycemic control and contribute to more favorable outcomes.
Insulin inhibits the hepatic glucose production and enhances peripheral glucose disposal thereby reducing blood-glucose concentration. It also inhibits lipolysis thereby preventing the formation of ketone bodies. A wide variety of insulin formulations is available as therapy. For many years, the vial and syringe were the standard means of delivering insulin. However, not all patients were comfortable with this method and this had serious implications on the compliance and glycemic control. The situation improved with the development of alternative means of delivery (such as insulin pens, insulin pumps, jet injectors).
In the present Phase I study a new pharmaceutical formulation / route of administration of insulin will be tested, using insulin wafers placed onto the mucosal tissues inside the mouth. Insulin from the wafer diffuses through the oral mucosa into the bloodstream. This oromucosal delivery is a convenient method for drug administration. The drug absorption occurs predominantly through the sublingual mucosa by diffusion of the active substance into the blood. Drug molecules absorbed by the oral mucosa thus avoid first pass metabolism. Oromucosal delivery is a simple and convenient method for drug administration even for people with visual impairment and /or dexterity problems leading to improved patient compliance.
The aim of this “Proof of Concept” Phase I study is to examine the pharmacokinetic and pharmacodynamic parameters of insulin from the wafer formulation in healthy male subjects. During the study, blood samples will be collected for up to 5 h to measure serum insulin and C-peptide of insulin. Safety will be monitored throughout the study as occurrence of adverse events, physical examination, clinical laboratory, vital signs, ECG, as well as local and overall tolerability. In this study, insulin effects will be determined using the Glucose-Clamp technique. To avoid hypoglycemic side effects, blood glucose levels will be monitored and maintained at a normal level (euglycemic clamp).
The insulin wafer is a mucoadhesive film formulation that clings to the mucosa inside the mouth. One insulin wafer contains 75 IU insulin. The study consists of Part 1, and Part 2, separated by a washout period of at least 6 days. Part 2 of the study will be performed only if satisfactory data are obtained in Part 1 regarding exposure to insulin (i.e. whether a sufficient amount of insulin has diffused from the insulin wafer into the blood stream).
In Part 1 of this study (single dose, open-label, parallel design), a comparison will be made of the blood insulin levels obtained after lingual/palatal administration (insulin wafer placed on the upper side of the tongue and under the hard palate) versus gingival administration (insulin wafer placed on the upper gum and the lower gum). Two wafers (i.e. a total single dose of 150 IU of insulin) will be used for each of the two investigated administration routes.
In Part 2 of this study (single dose, double-blind, double dummy, crossover design), the same healthy subjects who participated in Part 1 will receive two placebo wafers (not containing insulin) together with a single subcutaneous injection of 0.2 mL insulin solution (corresponding to 7.5 IU insulin) and, after a washout period of at least 6 days, again two placebo wafers together with a single subcutaneous injection of approximately 0.2 mL physiological saline. Results from Part 2 will be compared with those obtained in Part 1.
For each study participant the duration of Part 1 of the study, including the screening examination, is 22 days; for both periods of Part 2, including the post study examination, the duration is planned for 16 days. If only Part 1 of the study is performed, the duration is planned for 29 days, which includes the post study examination.

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Organizational Data

  •   DRKS00003127
  •   2011/07/12
  •   [---]*
  •   no
  •   Approved
  •   AM-2011-019, Ethik-Kommission bei der Landesärztekammer Baden-Württemberg
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Secondary IDs

  •   U1111-1122-3353 
  •   2010-022179-79 
  •   4036923 
  •   DRKS00000758;  (DRKS-ID Study Part 1 / Studienteil 1)
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Health Condition or Problem studied

  •   This is a Phase I study, involving healthy subjects. The study is designed as a "Proof of Concept" to evaluate oromucosal delivery of insulin, contained in a mucoadhesive wafer.

    The study population in this clinical study will not benefit from the treatment. Orosomucosal delivery of insulin may be of benefit to patients with Diabetes Mellitus.
  •   E10 -  Insulin-dependent diabetes mellitus
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Interventions/Observational Groups

  •   Lingual/palatal OR Gingival placebo wafers (depending on the results of Part 1 of the study) plus subcutaneously administered insulin (0.2 mL, 7.5 IU); N=12 healthy subjects.
  •   Lingual/palatal OR Gingival placebo wafers (depending on the results of Part 1 of the study) plus subcutaneously administered physiological saline (0.2 mL); N=12 healthy subjects.
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Double or multiple blind
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  •   Placebo
  •   Treatment
  •   Crossover
  •   I
  •   [---]*
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Primary Outcome

Part 2 of the study:
"Proof of concept" by comparing insulin delivery after oromucosal application of insulin-containing wafers (data from Part 1) with subcutaneous injection of insulin and placebo.

Glucose clamp:
Constant insulin infusion: up to 5 h after start administration with an infusion rate of up to 0.15 mU/kg min.
Glucose sampling (capillary blood sampling): approximately every 10 to 15 min for approximately 50 min prior to dosing (at least 5 samples), every 5 min during wafer application (at least 13 samples), after the end of the administration period every 15 to 30 min for up to 5 h after start of wafer administration (at least 16 samples).

Venous blood sampling for pharmacokinetics:
Blood samples (2.7 mL) for the determination of insulin and C-peptide concentrations in serum at -2.0, -1.5, -1.0, -0.5, 0 (=start of wafer administration), 0,083 (5 min), 0,167 (10 min), 0.25 (15 min), 0.33 (20 min), 0.42 (25 min), 0.5 (30 min), 0.75 (45 min), 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 h after start of administration (21 blood samples).

Venous blood sampling for pharmacodynamics:
Blood samples (2.7 mL) for the determination of glucose in plasma will be taken at -2.0, -1.5, -1.0, -0.5, 0 (=start of wafer administration), 0.083 (5 min), 0.167 (10 min), 0.25 (15 min), 0.33 (20 min), 0.42 (25 min), 0.5 (30 min), 0.75 (45 min), 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 after start of administration (21 blood samples).

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Secondary Outcome

Secondary objective is to assess the safety and tolerability of oromucosal application of insulin containing wafers. Adverse events, physical examination, clinical laboratory, vital signs, ECG, local and overall tolerability.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2011/07/20
  •   12
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Male
  •   18   Years
  •   45   Years
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Additional Inclusion Criteria

Male subjects of any ethnic origin between 18 and 45 years of age (inclusive);
Non-smokers;
In good general physical health, determined by medical history (including exclusion of first-degree family diabetes);
Physical examination, electrocardiogram (ECG),
vital signs, clinical laboratory tests;
Body Mass Index within 19 to 28 kg/m2 and body weight within 69.4 to 80.6 kg (75 kg ± 7.5%);
Fasting venous blood glucose between 70 and 110 mg/dL (inclusive).

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Exclusion Criteria

Subjects with tendency for gum bleeding, oromucosal lesions or other oromucosal diseases;
Subjects with a clinical history of allergic reactions against p-Hydroxy benzoic acid esters (PHB-esters);
Hypersensitivity to any of the ingredients of the investigational medicinal
product;
Any history of alcohol or drug abuse;
Any history of chronic gastritis or peptic ulcers;
Any history of chronic or recurrent metabolic, renal, hepatic, pulmonary,
gastrointestinal, neurological (esp. history of epileptic seizures), endocrinological, immunological, psychiatric or cardiovascular disease, myopathies and bleeding tendency;
Blood donation within 30 days prior to inclusion in this study;
Laboratory values outside the reference range that are of clinical relevance (e.g., suggesting an unknown disease and requiring further clinical evaluation assessed by the investigator) especially aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (gamma-GT).

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Addresses

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    • LTS Lohmann Therapie-Systeme AG
    • Lohmannstrasse 2
    • 56626  Andernach,
    • Germany
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    • CRS Clinical Research Services Mannheim GmbH
    • Mr.  MD  Wolfgang  Timmer 
    • Grenadierstrasse 1
    • 68167  Mannheim
    • Germany
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    • CRS Clinical Research Services Mannheim GmbH
    • Mr.  MD  Wolfgang  Timmer 
    • Grenadierstrasse 1
    • 68167  Mannheim
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Dienstsitz Berlin
    • Friedrichstraße 130 B
    • 10117  Berlin
    • Germany
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    • LTS Lohmann Therapie-Systeme AG
    • Lohmannstrasse 2
    • 56626  Andernach
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2012/11/12
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.