The number of patient-indicated painful crises in relation to total follow-up time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval. Also, the average number of crisis days per patient in relation to total follow-up time will be evaluated (including hospital admission days, see below).

A painful crisis will be defined as either (overlap is possible):

• When the box "Yes, I was in a crisis" is checked in a daily diary.
• Missing diary days that are immediately preceded and followed by crisis days or by hospital admission.
• A visit or admission to a hospital that lasted more than 4 hours for acute sickling-related pain, which was treated with orally or parenterally administered narcotics.
• An acute chest syndrome

The number of days with patient-indicated painful crises in relation to total follow-up time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval.

A painful crisis will be defined as either (overlap is possible):

• When the box "Yes, I was in a crisis" is checked in a daily diary.
• Missing diary days that are immediately preceded and followed by crisis days or by hospital admission.
• A visit or admission to a hospital that lasted more than 4 hours for acute sickling-related pain, which was treated with orally or parenterally administered narcotics.
• An acute chest syndrome

The average intensity of pain indicated on crisis days in daily life will be compared between the two groups. The intensity of pain will be calculated as the average pain score over all crisis days, using the highest scores indicated per day (either score over night or over day). Hospital days will be excluded from the analysis, as these scores often have not been completed fully during admission and the analysis is targeted at pain in daily life. Pain scores will be considered as continuous data with a normal distribution.

Painful crisis definition as above.

The number of sickle cell related hospital admissions in relation to total follow-up diary observation time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval.

Admissions will be verified using hospital medical records, if available. Hospital admission will be defined as:

• Every visit to a hospital that lasted more than 4 hours for acute sickling-related disease, which was treated with orally or parenterally administered narcotics.

The number of sickle cell related hospital admission days in relation to total follow-up diary observation time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval.

Admissions will be verified using hospital medical records, if available. Hospital admission will be defined as:

• Every visit to a hospital that lasted more than 4 hours for acute sickling-related disease, which was treated with orally or parenterally administered narcotics.

The time in days from randomization to first painful crisis (patient-defined) and hospital admission for painful crisis will be expressed in cumulative event rates, estimated by Kaplan-Meier analysis.

The time in days from randomization to first painful crisis (patient-defined) and hospital admission for painful crisis will be expressed in cumulative event rates, estimated by Kaplan-Meier analysis.

In adults this will be assessed with SF36-forms, a short-form health survey that has been proven to be valid and reliable in the black population.46 In children from 12 to 18 years old, we will use the PedsQL questionnaire, often used to assess quality of life in children, also validated in SCD patients

The societal costs of pain care with the use of NAC, in the intervention group, will be compared to the societal costs of current pain care in the control group. Estimates of unit costs will be based on calculation of real costs of pain care.

Generated direct medical costs will be recorded in the case record forms and by means of the Medical Cost Questionnaire (see appendix). Indirect costs arising from losses in productivity will be assessed by means of the Productivity Cost Questionnaire (see appendix) and will be calculated by means of the friction cost method.

This will be assessed via the monthly adverse events reports. The frequency of registered adverse events and/or a serious adverse events will be reported per treatment arm, and compared between the two intervention groups.

The incidence rate of analgesic usage will be defined as the proportion of pain days with reported analgesic use on the total number of pain days (excluding observation days with no reported pain). This proportion will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval.

The number of patients with sickle cell related complications (i.e. acute chest syndrome, stroke etc.) will be reported per treatment arm, and compared between the two intervention groups.

The related incidence of SCD complications;

• Acute chest syndrome
• Priapism
• Hepatic sequestration
• Splenic sequestration
• Cerebrovascular accident
• Leg ulcer
• Symptomatic avascular osteonecrosis

These complications will be assessed monthly by using hospital medical records.

Compliance of use of study medication will primarily be checked by pill counts (number administered versus number returned). Compliance will be expressed as the proportion of tablets remaining, compared to the number of tablets that should have been taken based on a prescription of 2 tablets per day and the total number of observation days per patient.

We additionally aim to evaluate compliance by N-acetylcysteine plasma concentration measurements in blood samples drawn at T0, T3 and T6 in the intervention group, and assess mean change from baseline in the intervention group. This outcome may be used as alternative parameter for patient compliance if pill counts do not suffice.