979

Biotest AG

Landsteinerstr. 5, Dreieich, Germany, 63303

Daniela Zipp, Biotest AG, +49 6103 801 255 , daniela.zipp@biotest.com

Daniela Zipp, Biotest AG, +49 6103 801 255 , daniela.zipp@biotest.com

No

No

No

Final

16 Oct 2014

Yes

05 Aug 2013

Yes

16 Oct 2013

Yes

Is to investigate dose-response information on efficacy. Primary efficacy variable is ACR20 (at Week 13).

The patient had to give written consent to participate in the trial by signing and dating the informed consent form (ICF) before screening. Any new and relevant information that evolved during the course of the trial concerning the investigational medicinal product (IMP), alternative treatments, or the risk/benefit ratio was communicated to the patient. After SC administration the patient was asked to stay at the investigational site for at least 2 hours to cover the potential risk of a type I hypersensitivity reaction. Therefore, intensive care measures had to be available. Patients should be informed that such reactions are possible and prompt medical attention should be sought if allergic reactions occur. After administration of the last dose of the IMP patients were observed for a 12-week follow-up period on a regular outpatient basis. All these patients had in addition a safety follow-up visit at Week 24. Treatment is discontinued if at least one of the following three criteria are met for two consecutive weekly assessments. • CD3CD4 cell count ≤ 200 cells/μl or • CD3CD4 cell count < 50% of individual baseline count or • Total lymphocyte count < 50% of individual baseline count The treatment will be discontinued for male patients in case: • TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH) or testoste-rone levels are outside the normal range and • The investigator assesses these changes as compared to baseline as clinically relevant for 2 consecutive measurements. Other reasons for treatment discontinuation are: • Prolonged lymphopenia at two consecutive weekly visits • Lymphopenia is defined as < 1000 lymphocytes / μl (< 1.000 * 109 lymphocytes / l) in a whole blood specimen. • Anaphylactic or other serious allergic reaction Patients withdrawn from treatment should be followed up for at least 2 additional weeks and should . In case of an AE, the withdrawn patient should be followed up until the AE is resolved or in a steady state.

21 Dec 2010

No

No

Spain: 1

Czech Republic: 49

Germany: 8

Hungary: 2

Italy: 2

Latvia: 10

Poland: 56

128

128

0

0

0

0

0

0

101

27

0

Controlled Treatment Period (overall period)

Randomised - controlled

All study staff at the investigational site and study personnel at the sponsor / clinical research organization(s) involved in the conduct of the study remained blinded until study unblinding. Plasma concentrations of BT061 was determined at Biotest only after the blinded data review meeting (BDRM). The independent statistician, independent laboratory specialists and the IDRB members had access to such data before the BDRM. Unblinded personnel were not involved in any analysis.

Yes

Placebo

Solution for injection

Subcutaneous use

2 ml placebo (0 mg/ml BT061) (2 vials) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (placebo) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

BT061 25 mg

Solution for injection

Subcutaneous use

25 mg BT061 in 2 ml (1 ml 25mg/ml BT061 + 1 ml placebo 0 mg/ml BT061) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (BT061) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

BT061 50 mg

Solution for injection

Subcutaneous use

50 mg BT061 in 2 ml (1 ml 50 mg/ml BT061 + 1 ml placebo 0 mg/ml BT061) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (BT061) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

BT061 75 mg

Solution for injection

Subcutaneous use

75 mg BT061 in 2 ml (1 ml 25 mg/ml BT061 + 1 ml 50 mg/ml BT061) was administered subcutaneously weekly for a 12-week period (in total 12 applications). The IMP (BT061) was administered by the investigator or designated study staff according to the randomized assigned treatment group. 1 ml of each vial is injected at two different abdominal SC sites. Both SC doses of 1 ml volume each are administered undiluted and slowly in the region of the anterior abdomen into an area of intact skin.

Placebo

BT061 25 mg

BT061 50 mg

BT061 75 mg

All patients treated analysis set

All patients who received at least a single dose of study medication (IMP).

Full analysis set

All patients who received at least one dose of IMP and have at least one postbaseline assessment with respect to the efficacy parameters.

Per-protocol (PP) analysis set

All patients of the full analysis set without any major protocol violations as defined during the blinded data review meeting. Patients with major protocol deviations or incomplete documentation of relevant data will be excluded from the PP analysis. Patients who miss more than two doses of the IMP do not qualify for the perprotocol analysis set. In any case patients must have received the last two IMP injections of Week 11 and Week 12 to qualify for the PP set.

PK analysis set

Patients will be considered evaluable for PK analysis if they received at least one dose of BT061, and if they have at least one post-treatment plasma concentration measure of BT061.

Placebo

BT061 25 mg

BT061 50 mg

BT061 75 mg

All patients treated analysis set

All patients who received at least a single dose of study medication (IMP).

Full analysis set

All patients who received at least one dose of IMP and have at least one postbaseline assessment with respect to the efficacy parameters.

Per-protocol (PP) analysis set

All patients of the full analysis set without any major protocol violations as defined during the blinded data review meeting. Patients with major protocol deviations or incomplete documentation of relevant data will be excluded from the PP analysis. Patients who miss more than two doses of the IMP do not qualify for the perprotocol analysis set. In any case patients must have received the last two IMP injections of Week 11 and Week 12 to qualify for the PP set.

PK analysis set

Patients will be considered evaluable for PK analysis if they received at least one dose of BT061, and if they have at least one post-treatment plasma concentration measure of BT061.

The primary objective of this study was to investigate dose-response information on efficacy using the ACR20 response criteria after 12 weeks of treatment at study Week 13 (one week after end of treatment). The impact of the IMP on rheumatoid arthritis (RA) disease activity was evaluated by the difference between pre-treatment (baseline) disease activity and one week post-treatment (Week 13) disease activity. An ACR20 response was defined as at least 20% improvement in both the tender joint count and the swollen joint count and at least 20% improvement in 3 of the 5 other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ).

Primary

From baseline to study week 13 ( one week after 12 weeks of treatment)

The primary analysis is the final analysis of the 2 groups (BT061 25 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.

BT061 25 mg v Placebo

64

Pre-specified

1.65

2-sided

The primary analysis is the final analysis of the 2 groups (BT061 50 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.

BT061 50 mg v Placebo

64

Pre-specified

1.65

2-sided

The primary analysis is the final analysis of the 2 groups (BT061 75 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.

BT061 75 mg v Placebo

63

Pre-specified

1.21

2-sided

ACR50 response was derived using last observation carried forward and Non-responder Imputation. An ACR50 response was defined as at least 50% improvement in both the tender joint count and the swollen joint count and at least 50% improvement in 3 of the 5 other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ).

Secondary

From baseline to study Week 13

The final analysis of the 2 groups (BT061 25 mg and placebo) of ACR50 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.

BT061 25 mg v Placebo

64

Pre-specified

1.96

2-sided

The primary analysis is the final analysis of the 2 groups (BT061 50 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.

BT061 50 mg v Placebo

64

Pre-specified

1

2-sided

The primary analysis is the final analysis of the 2 groups (BT061 75 mg and placebo) of ACR20 response at Week 13 (using last observation carried forward (LOCF)) which was analysed using logistic regression adjusted for centre effect. The adjusted odds ratio (OR) with 95% confidence interval (CI) and the Wald p-value were calculated for the selected active treatment group against the placebo group together with the significance of the centre effect.

BT061 75 mg v Placebo

63

Pre-specified

3.85

2-sided

ACR70 response was derived using last observation carried forward and Non-responder Imputation. An ACR70 response was defined as at least 70% improvement in both the tender joint count and the swollen joint count and at least 70% improvement in 3 of the 5 other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ).

Secondary

From baseline to study Week 13

The hybrid ACR is derived at each post-baseline visit from the 7 core set items (components: the tender joint count and the swollen joint count and other core set measures including CRP and/or ESR, Investigator assessment of disease activity, Patient assessment of disease activity, Patient assessment of pain, Health Assessment Questionnaire (HAQ)) by the following steps: 1. For each component: „Bound %change‟ = percentage improvement (defined above) provided this is >-100%; -100% otherwise (Thus, a deterioration can never go beyond -100%.) 2. „Mean %change‟ = mean of the 7 „bound %change‟ values classified as <20, 20-<50, 50-<70 or 70+. 3. ACR status = „not ACR20‟ or „ACR20 but not ACR50‟ or „ACR50 but not ACR70‟ or „ACR70‟ based on the definitions of ACR20, ACR50 and ACR70.

Secondary

From baseline to study Week 13

Disease activity score for 28 joints (DAS28) combines information from swollen joints, tender joints, acute phase response, and general health into one continuous measure of RA inflammation. DAS28 criteria are a modified version of DAS, which has a reduced and non-graded joint count. It consists of a 28 tender joint count (range 0 to 28), a 28 swollen joint count (range 0 to 28), ESR, and an optional general health assessment on a VAS (range 0 to 100), which will be assessed for this study. DAS28 has a continuous scale ranging from 0 to 10. The level of disease activity is interpreted as low (DAS28 ≤ 3.2), moderate (3.2 < DAS28 ≤ 5.1), and high (DAS28 > 5.1). Higher DAS28 scores means worse disease activity.

Secondary

From baseline to study Week 13

The EULAR response is defined at each post-baseline visit in terms of Disease Activity Scores (DAS28) change from baseline. If the score is missing it will be derived using LOCF. If DAS28 at endpoint ≤ 3.2, the response was categorized based on improvement (reduction) in DAS28 from baseline >1.2 (Good), > 0.6 and ≤ 1.2 (Moderate) and ≤ 0.6 (None). If DAS28 at endpoint > 3.2 and ≤ 5.1, the response was categorized based on improvement (reduction) in DAS28 from baseline >1.2 (Moderate), > 0.6 and ≤ 1.2 (Moderate) and ≤ 0.6 (None). If DAS28 at endpoint > 5.1, the response was categorized based on improvement (reduction) in DAS28 from baseline >1.2 (Moderate), > 0.6 and ≤ 1.2 (None) and ≤ 0.6 (None).

Secondary

From baseline to study Week 13

Clinical Disease Activity Index (CDAI) was calculated at each post-baseline visit as the sum of the number of tender joints (t28) from the 28 joints shaded on the CRF, the number of swollen joints (sw28), the disease activity (patient‟s global assessment) and the disease activity (physician‟s global assessment).

Secondary

From baseline to study Week 13

The Simplified Disease Activity Index (SDAI) was calculated at each post-baseline visit as the sum of the Clinical Disease Activity Index (CDAI) and the C-reactive protein (CRP) (in mg/dL). If any components of the SDAI are missing then the score will be missing. If the score is missing it will be derived using LOCF.

Secondary

From baseline to study Week 13

Single Component of ACR for RA assesses: 68 joints for tenderness. Mean levels and percentage changes from baseline were plotted against weeks since start of treatment by treatment group. Minus percentage changes from baseline means improvement and plus change means worsening.

Secondary

From baseline to study Week 13

Single Component of ACR for RA assesses: 68 joints for swollenness. Mean levels and percentage changes from baseline were plotted against weeks since start of treatment by treatment group. Minus percentage changes from baseline means improvement and plus change means worsening.

Secondary

From baseline to study Week 13

Mean levels of C-reactive protein (CRP in mg/L) and percentage changes from baseline will be plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

Erythrocyte Sedimentation Rate (ESR) Mean levels and percentage changes from baseline will be plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

Mean levels and percentage changes from baseline for ACR component (VAS for global disease activity (investigator)) will be plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

Mean levels and percentage changes from baseline for ACR component (VAS for global disease activity (patient)) will be plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

Mean levels and percentage changes from baseline for ACR component (VAS for Patient’s Pain) will be plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

Mean levels and percentage changes from baseline for ACR component (Health Assessment Questionnaire) will be plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

Mean levels and percent changes of Functional Assessment Of Chronic Illness Therapy (FACIT) - Fatigue Questionnaire were plotted against weeks since start of treatment by treatment group.

Secondary

From baseline to study Week 13

From signed informed consent to the end of follow up (up to 30 weeks)

Only serious nontreatment- emergent AEs that were related to study procedures have been collected. An AE that occurs from the time the patient receives his/her first dose of study drug until his/her final follow up visit, was treatment-emergen AE (TEAE). All TEAEs will be collected.

14.0

All Patients Treated Analysis Set

Placebo

BT061 25 mg

BT061 50 mg

BT061 75 mg