A Dose-Range Finding Study for ALX-0061 Combination Therapy in Subjects With Rheumatoid Arthritis

ACR 20 response is defined as:

• 20% improvement in tender joint count (TJC; 68 joints) relative to Week 0 AND
• 20% improvement in swollen joint count (SJC; 66 joints) relative to Week 0 AND
• 20% improvement in 3 of the following 5 areas relative to Week 0:

• Subject's Assessment of Pain (100 mm - visual analogue scale [VAS])
• Subject's Global Assessment of Disease Activity (VASPA)
• Physician's Global Assessment of Disease Activity (VASPHA)
• Subject's assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI)
• C-reactive protein (CRP) level

The primary endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing ACR20 response at Week 12 were treated as non responders.

ACR 20 response is defined as:

• 20% improvement in tender joint count (TJC; 68 joints) relative to Week 0 AND
• 20% improvement in swollen joint count (SJC; 66 joints) relative to Week 0 AND
• 20% improvement in 3 of the following 5 areas relative to Week 0:

• Subject's Assessment of Pain (100 mm - visual analogue scale [VAS])
• Subject's Global Assessment of Disease Activity (VASPA)
• Physician's Global Assessment of Disease Activity (VASPHA)
• Subject's assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI)
• C-reactive protein (CRP) level

This endpoint was analyzed using NRI, i.e., subjects with missing response at Week 24 were treated as non responders.

ACR50 response is defined as:

• 50% improvement in TJC (68 joints) relative to Week 0 AND
• 50% improvement in SJC (66 joints) relative to Week 0 AND
• 50% improvement in 3 of the following 5 areas relative to Week 0:

• Subject's Assessment of Pain (100 mm - VAS)
• Subject's Global Assessment of Disease Activity (VASPA)
• Physician's Global Assessment of Disease Activity (VASPHA)
• Subject's assessment of physical function as measured by HAQ-DI
• CRP level

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

ACR70 response is defined as:

• 70% improvement in TJC (68 joints) relative to Week 0 AND
• 70% improvement in SJC (66 joints) relative to Week 0 AND
• 70% improvement in 3 of the following 5 areas relative to Week 0:

• Subject's Assessment of Pain (100 mm - VAS)
• Subject's Global Assessment of Disease Activity (VASPA)
• Physician's Global Assessment of Disease Activity (VASPHA)
• Subject's assessment of physical function as measured by HAQ-DI
• CRP level

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

DAS28(CRP) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.36 × ln[CRP+1]) + (0.014 × VASPA) + 0.96

Low disease activity = 2.6 ≤ DAS28 ≤ 3.2

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) +(0.014 × VASPA)

Low disease activity = 2.6 ≤ DAS28 ≤ 3.2

Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

SDAI = TJC28 + SJC28 + Patient's Global Assessment of Disease Activity (VASPA) + Physician's Global Assessment of Disease Activity (VASPHA) + CRP (mg/dL)

Low disease activity: 3.3 < SDAI ≤ 11.0

Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

CDAI = TJC28 + SJC28 + VASPA + VASPHA

Low disease activity: 2.8 < CDAI ≤ 10

Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

EULAR good response is defined as an improvement of >1.2 in DAS28 (CRP) relative to baseline.

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) +(0.014 × VASPA)

Remission = DAS28(ESR) < 2.6

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

SDAI = TJC28 + SJC28 + VASPA + VASPHA + CRP (mg/dL)

Remission: SDAI ≤ 3.3

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

CDAI = TJC28 + SJC28 + VASPA + VASPHA

Remission: CDAI ≤ 2.8

This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.

Boolean remission: tender joint count (TJC)28 ≤ 1 and swollen joint count (SJC)28 ≤ 1 and VASPA (cm) ≤ 1 and CRP (mg/dL) ≤ 1

This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.

The HAQ-DI is a 20-question instrument which assesses the degree of difficulty the subject had in accomplishing tasks in 8 functional areas over the previous week. The 8 areas are: dressing and grooming, hygiene, arising, reach, eating, grip, walking, common daily activities. Within each area, subjects report the amount of difficulty they have in performing the specific items. There are 4 response options ranging from: 0 = No Difficulty, 1 = With Some Difficulty, 2 = With Much Difficulty, 3 = Unable to Do. The 8 areas are each given a single score equal to the maximum value of their component activities (0, 1, 2, or 3). The sum of the area scores is then divided by the number of areas answered to obtain the final HAQ score (rounded to the nearest value evenly divisible by 0.125). The final HAQ-DI score ranges from 0 to 3. A high score means a high degree of disability (=worse outcome).

Missing values were imputed with the last non-missing observation.

The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.

The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.

The FACIT Measurement System is a collection of health-related quality of life questionnaires that assess multidimensional health status in people with various chronic illnesses. The FACIT Fatigue Scale is a short, 13-item, easy to administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued). To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52. Items are reverse scored when appropriate to provide a scale in which higher scores represent better functioning or less fatigue.

ALX-0061 concentrations were only measured in samples of subjects randomized to any of the ALX-0061 treatment arms. Samples were taken predose at the concerned visits.

Values below the limit of quantification are imputed with the lower limit of quantification (LLOQ).