Clinical Trials in Still's disease (sJIA/AOSD)

Fabrizio de Benedetti

Rheumatology, Children Hospital Bambino Gesu', Rome - Italy

Clinical trials in Still's disease

Present scenario

• · IL-1 or IL-6 inhibitors are very efficacious in 70-80% of patients
• · Early treatment with biologics is more and more standard of care with IL-1 and IL-6 inhibitors being widely available

Patient/Parent perspectives (physicians also)

• · Acceptability of 'experimental' drugs vs established approach
• · Acceptability of randomization (experimental drug vs placebo or experimental drug vs active control)
Clinical trials in Still's disease

Present scenario

• · IL-1 or IL-6 inhibitors are very efficacious in 70-80% of patients
• · Early treatment with biologics is more and more standard of care with IL-1 and IL-6 inhibitors being widely available

Patient/Parent perspectives (physicians also)

• · Acceptability of 'experimental' drugs vs established approach
• · Acceptability of randomization (experimental drug vs placebo or experimental drug vs active control)


Refractory or D2T Still' disease

Refractory (D2T) Still's disease

• · Persistent chronic arthritis (with or without active syst features)
• · Relapsing/smouldering MAS with or without LD
• · Acute MAS flare (with or without LD)
• · Difficult if not impossible to lump them in the same trial
• · Overall they are very rare
• · Only one trial is doable
(with or without active systemic features)

Refractory (D2T) Still's disease 1. persistent chronic arthritis

Classification criteria: OK with ILAR, Yamaguchi, provisional PRINTO Response criteria:

• · OK with JIA-ACR response + absence of fever, systJADAS (merging adults and children criteria)
• · Tapering/withdrawal of background treatment (e.g. GC)

Eligible for ongoing trials in pcJIA (e.g. Jak inhibitors), only if systemic symptoms are absent

·

Need new MoA (limited safety data)

·

12 and older

🡪

PK modeling for dosing in <12yo

·

Sample size

·

Randomization (placebo? Active control?)

·

Open label

·

External (historical) controls

(with or without active systemic features)

Refractory (D2T) Still's disease 1. persistent chronic arthritis

Classification criteria: OK with ILAR, Yamaguchi, provisional PRINTO

Response criteria:

• · OK with JIA-ACR response + absence of fever, systJADAS (merging adults and children criteria
• · Tapering/withdrawal of background treatment (e.g. GC)
• · Eligible for ongoing trials in JIA (e.g. Jak inhibitors), only if systemic symptoms are absent
• · Need new MoA (limited safety data)
• · 12 and older 🡪 PK modeling for dosing in <12yo
• · Sample size
• · Randomization (placebo? Active control?)
• · Open label
• · External (historical) controls
Refractory (D2T) Still's disease 2. Relapsing/smouldering MAS with or without LD

Syst features - little, if any arthritis

Lung disease (LD)

Relapsing and/or smouldering MAS

Classification criteria

·

NOT OK with ILAR, might be OK with Yamaguchi or provisional PRINTO

• · Largely overlapping subset
• · Mostly IL-18 high
• · Many reccurrent eosinophilia
• · Many DRB1*15 carriers

·

Response criteria

·

NOT OK with JIA-ACR response + absence of fever

·

MAYBE syst-JADAS (merging adults and children criteria)

·

Tapering/withdrawal of background treatment (e.g. GC, biologics)

Refractory (D2T) Still's disease 2. Relapsing/smouldering MAS with or without LD

Syst features - little, if any arthritis Lung disease (LD) Relapsing and/or smouldering MAS

• · Largely overlapping subset
• · Mostly IL-18 high
• · Many recurrent eosinophilia
• · Many DRB1*15 carriers

Classification criteria

• · NOT OK with ILAR, OK with Yamaguchi or provisional PRINTO
• · Response criteria
• · NOT OK with JIA-ACR response + absence of fever
• · MAYBE syst-JADAS (merging adults and children criteria?)
• · Need to capture MAS features (MAS remission?)
• · Need to capture LD course (O 2 requirement, O 2 overnight saturation)
• · Tapering/withdrawal of background treatment (e.g. GC, biologics)
Refractory (D2T) Still's disease 2. Relapsing/smouldering MAS with or without LD

Syst features - little, if any arthritis

Lung disease (LD)

Relapsing and/or smouldering MAS

• · Design
• · Placebo controlled unethical
• · No active comparable available (no SoC)
• · Sample size
• · Historical controls
• · Largely overlapping subset
• · Mostly IL-18 high
• · Many reccurrent eosinophilia
• · Many DRB1*15 carriers
Refractory (D2T) Still's disease 3. Acute MAS flare (with or without LD)

Classification criteria

• · OK with 2016 MAS criteria
• · NOT OK with ILAR because severe MAS present often at disease onset
• · OK with Yamaguchi or provisional PRINTO

Response criteria

• · MAS remission as defined in the emapalumab trial -> no formal validation
• · Tapering/withdrawal of background treatment (e.g. GC, biologics)

Design

·

Placebo controlled unethical

·

No active comparable available (SoC?)

·

Background treatment for Still's disease

·

Sample size

·

Historical controls

Refractory (D2T) Still's disease 3. Acute MAS flare (with or without LD)

Classification criteria

• · OK with 2016 MAS criteria
• · NOT OK with ILAR because severe MAS present often at disease onset
• · OK with Yamaguchi or provisional PRINTO

Response criteria

• · MAS remission as defined in the emapalumab trial -> no formal validation
• · Tapering/withdrawal of background treatment (e.g. GC, biologics)

Design

• · Placebo controlled unethical
• · No active comparable available (SoC?)
• · Background treatment for Still's disease
• · Sample size
• · Historical controls